Azulene derivatives and salts thereof

ABSTRACT

The present invention provides an azulene derivative and a salt thereof, wherein an azulene ring is bonded to a benzene ring directly or via a lower alkylene which may be substituted with a halogen atom and the benzene ring is directly bonded to the glucose residue, and it is usable as a Na + -glucose cotransporter inhibitor, especially for a therapeutic and/or preventive agent for diabetes such as insulin-dependent diabetes (type 1 diabetes) and insulin-independent diabetes (type 2 diabetes), as well as diabetes-related diseases such as insulin-resistant diseases and obesity.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Phase Application based onPCT/JP2003/009868, filed on Aug. 4, 2003, the content of which isincorporated herein by reference, and claims the priority of JapanesePatent Application Nos. 2002-226869, filed on Aug. 5, 2002, and2003-130991, filed on May 9, 2003.

FIELD OF THE INVENTION

The present invention relates to an azulene derivative of a specificchemical formula and a salt thereof. More particularly, the presentinvention relates to an azulene derivative which effectively treats orprevents diabetes such as insulin-dependent diabetes (type 1 diabetes),and insulin-independent diabetes (type 2 diabetes), as well as variousdiabetes-related diseases such as insulin-resistant diseases andobesity, for example, as a pharmaceutical, particularly as a Na⁺-glucosecotransporter inhibitor, and to a salt thereof.

BACKGROUND OF THE INVENTION

In recent years, a pharmaceutical to inhibit a Na⁺-glucose cotransporter(SGLT) in the intestinal tract and kidney to reabsorb glucose (aNa⁺-glucose cotransporter inhibitor) has been demanded as anantidiabetic agent to rapidly normalize hyperglycemia and improve theenergy balance in the body. Such a Na⁺-glucose cotransporter inhibitorhas been expected as an excellent pharmaceutical for treating orpreventing diabetes such as insulin-dependent diabetes (type 1 diabetes)and insulin-independent diabetes (type 2 diabetes), as well asdiabetes-related diseases such as insulin-resistant diseases andobesity.

As compounds used as the Na⁺-glucose cotransporter inhibitor, phloridzindescribed in Welch, C. A. et al. (J. Natr., 1989, 119(11) 1698) and asynthetic O-glycoside described in Hongu, M. et al. (Chem. Pharm. Bull.,1998, 46(1) 22) and JP-A-11-21243 are known, for example. Thesecompounds are reported to discharge excess blood glucose into urine andreduce the level of blood glucose by inhibiting a Na⁺-glucosecotransporter in the kidney.

However, since any of these compounds are an O-glycoside comprising anO-glucoside bond formed between glucose and an aglycon moiety, it has aproblem that the hypoglycemic effect is disappeared due to hydrolysis ofO-glucoside bond by glucosidase or the like in the small intestine whenorally absorbed.

Phloretin, an aglycon moiety of phloridzin, is known to highly inhibit afacilitated diffusion-type glucose transporter. For example, it isreported that the cerebral glucose concentration decreases whenphloretin is administered to the vein of a rat (e.g. Stroke, 1983, 14,388). Phloretin is also known to inhibit a vitamin C transporter (Wang,Y. et al., Biochem. Biophys. Res. Commun., 2000, 267, 488–494).

Therefore, an attempt has been made to use a C-glycoside prepared byconverting oxygen in the glucoside bond of the O-glycoside to carbon asthe Na⁺-glucose cotransporter inhibitor.

For example, JP-A-2001-288178 (hereinafter referred to as PatentDocument 1) describes that a compound of the following formula has theeffect of inhibiting a Na⁺-glucose cotransporter and is useful as atreating agent or preventing agent for diabetes and a hypoglycemicagent.

wherein R₁ represents H, OH, lower alkyl group, —O-lower alkyl group, orthe like, R₂ represents H, —COO-lower alkyl group, or the like, R₅represents —CH₂OH, —CH₂OCOO-lower alkyl group, or the like, A₁represents pyridine, furan, thiophene, quinoline, indole, or the like, nis 0, 1, 2, or 3, and m is 0 or 1 (See Patent Document 1 for furtherdetails on the symbols of the above formula).

In addition, the pamphlet of WO 01/27128 (hereinafter referred to PatentDocument 2) describes that a compound of the following formula can beused as the Na⁺-glucose cotransporter inhibitor to treat obesity or type2 diabetes.

wherein R¹, R², and R^(2a) individually represent a hydrogen atom, OH,OR⁵, alkyl, CF₃, OCHF₂, OCHF₃, or the like, R³ and R⁴ individuallyrepresent a hydrogen atom, OH, OR^(5a), —O-aryl, —O—CH₂-aryl, alkyl,cycloalkyl, CF₃, or the like, A represents O, S, NH, or (CH₂)_(n), and nis 0, 1, 2, or 3 (See Patent Document 2 for further details on thesymbols of the above formula).

As explained above, the C-glycoside is useful to a certain extent fortreating diabetes due to the effect of inhibiting a Na⁺-glucosecotransporter. However, due to the recent rise in incidence of diabeteswhich is a lifestyle-related disease and could even be called a nationaldisease, a compound having a chemical structure different from that of aknown compound and showing the effect of inhibiting a Na⁺-glucosecotransporter more rapidly and more significantly has been increasinglydesired for the clinical practice of diabetes treatment or the like.

DISCLOSURE OF THE INVENTION

The present inventors have conducted extensive studies about a compoundwith a benzene ring directly bonded with a glucose residue and havingthe effect of inhibiting a Na⁺-glucose cotransporter. As a result, theinventors have found that a compound (an azulene derivative) having anazulene ring bonded to a benzene ring directly or via a lower alkylene(-A-) which may be substituted with a halogen atom, with the benzenering being directly bonded to a glucose residue, shown by the followingformula (I), has a significant effect of inhibiting a Na⁺-glucosecotransporter. Specifically, the present invention provides a compoundof the following formula (I) and a salt thereof (hereinafter bothreferred to as “compound of the present invention”). The compound of thepresent invention can be suitably used as a Na⁺-glucose cotransporterinhibitor using the compound as an active ingredient, particularly as atherapeutic agent and/or preventive agent for diabetes.

The chemical structure of the compound of the present invention differsfrom those of Patent Documents 1 and 2 in that the compound of thepresent invention has an azulene ring, for example.

wherein R¹ to R⁴ individually represent a hydrogen atom, an optionallysubstituted lower alkyl, —C(═O)-optionally substituted lower alkyl, or-optionally substituted lower alkylene-optionally substituted aryl,

R⁵ to R¹² individually represent a hydrogen atom, an optionallysubstituted lower alkyl, halogen atom, —OH, —O—optionally substitutedlower alkyl, -optionally substituted lower alkylene-OH, -optionallysubstituted lower alkylene-O-optionally substituted lower alkyl,—O-optionally substituted lower alkylene-O-optionally substituted loweralkyl, —O-optionally substituted lower alkylene-optionally substitutedaryl, -optionally substituted lower alkylene-O—C(═O)-optionallysubstituted lower alkyl, —COOH, nitro, cyano, amino, substituted amino,or —C(═O)—O-optionally substituted lower alkyl, and

A represents a bond or an optionally substituted lower alkylene,

wherein -A- may be bonded to any one of the positions 1–8 of the azulenering, and any two of R⁵, R⁶, and R⁷ may form a benzene ring togetherwith the adjacent carbon atoms.

The term “optionally substituted” used for the definitions of the groupsrepresented by R¹ to R⁴, R⁵to R¹², and A indicates the groups inquestion may be either substituted or unsubstituted with a halogen atom,—OH, -lower alkylene-OH, —COOH, —C(═O)—O-lower alkyl, nitro, cyano,amino, or substituted amino. A halogen atom, —OH, and —COOH arepreferable as a substituent.

The optionally substituted lower alkyl, —C(═O)-optionally substitutedlower alkyl, and -optionally substituted lower alkylene-optionallysubstituted aryl represented by R¹ to R⁴ in the above formula (I) arepreferably a lower alkyl, —C(═O)-lower alkyl, and -lower alkylene-aryl,respectively. The optionally substituted lower alkyl, —O-optionallysubstituted lower alkyl, -optionally substituted lower alkylene-OH,-optionally substituted lower alkylene-O-optionally substituted loweralkyl, —O-optionally substituted lower alkylene-O-optionally substitutedlower alkyl, —O-optionally substituted lower alkylene-optionallysubstituted aryl, -optionally substituted loweralkylene-O—C(═O)-optionally substituted lower alkyl, and—C(═O)—O-optionally substituted lower alkyl represented by R⁵ to R¹² inthe formula (I) are preferably a lower alkyl, —O-lower alkyl, -loweralkylene-OH, -lower alkylene-O-lower alkyl, —O-lower alkylene-O-loweralkyl, —O-lower alkylene-aryl, -lower alkylene-O—C(═O)-lower alkyl, and—C(═O)—O-lower alkyl, respectively. The optionally substituted loweralkylene represented by A in the above formula (I) is preferably a loweralkylene or a halogen-substituted lower alkylene.

In the compound of the present invention, the group represented by A ofthe above formula (I) is preferably a lower alkylene, and particularlypreferably a methylene.

The groups R¹–R⁴ of the above formula (I) are preferably a hydrogenatom.

The azulene derivative of the above formula (I) may be preferably anyone of compounds selected from the group consisting of1,5-anhydro-1-[3-(azulen-2-ylmethyl)phenyl]hexytol,1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-methoxyphenyl]hexytol,1,5-anhydro-1-[3-(azulen-2-ylmethyl)-5-methoxyphenyl]hexytol,1,5-anhydro-1-[3-(azulen-2-ylmethyl)-4-methoxyphenyl]hexytol,1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-ethoxyphenyl]hexytol,1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-methylphenyl]hexytol,1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-hydroxyphenyl]hexytol,1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-fluorophenyl]hexytol,1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2,4-dimethoxyphenyl]hexytol, and1,5-anhydro-1-[4-(azulen-2-ylmethyl)-1-methoxy-2-naphthyl]hexytol.

The present invention also provides a pharmaceutical compositioncontaining the above azulene derivative or the salt thereof as an activeingredient and pharmaceutically acceptable adjuvants.

The pharmaceutical composition of the present invention is effectivelyused for a Na⁺-glucose cotransporter inhibitor or a preventing agent ortherapeutic agent for diabetes and diabetic complications.

The present invention further provides use of the azulene derivative orthe salt thereof for producing a Na⁺-glucose cotransporter inhibitor ora preventive agent and/or therapeutic agent for diabetes and diabeticcomplications.

The present invention further provides a therapeutic method for diabetesand diabetic complications comprising administering an effective amountof the above azulene derivative or the salt thereof to a patient.

In the definition of the formulas in this specification, “lower” refersto a linear or branched-carbon chain having 1–6 carbon atoms, unlessotherwise specified. Accordingly, examples of a “lower alkyl” includelinear or branched alkyls having 1–6 carbon atoms such as a methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl,isopentyl, hexyl, and isohexyl. Of these, alkyls having 1–3 carbon atomsare preferable, with a methyl and ethyl being particularly preferable.

As a “lower alkylene,” inaddition to a methylene, ethylene, propylene,and butylene, a branched lower alkylene may be used. Of these, amethylene and ethylene are preferable, with a methylene beingparticularly preferable.

As a “halogen atom,” a fluorine atom, chlorine atom, bromine atom, oriodine atom can be given, with a chlorine atom and bromine atom beingpreferable. As a “halogen-substituted lower alkyl” or“halogen-substituted lower alkylene,” a lower alkyl or lower alkylenesubstituted with the above halogen atom can be given, with a lower alkylor lower alkylene substituted with one or more fluorine atoms beingparticularly preferable.

An “aryl” refers to a monocyclic to tricyclic aromatic hydrocarbon grouphaving 6–14 carbon atoms. Examples of the aryl include a phenyl,naphthyl, anthranyl, and phenanthryl, with a phenyl and naphthyl beingparticularly preferable. As a “-lower alkylene-aryl,” a benzyl andphenethyl are preferable.

As a “substituted amino,” an amino group of which one or two hydrogenatoms are substituted with the lower alkyl, an acyl, carbamoyl, orcarbamate (NH₂—C(═O)—O—) can be given. As the “acyl,” a formyl, acetyl,propionyl, butyryl, valeryl, pivaloyl, or the like can be given, with anacetyl being particularly preferable.

-A- in the above formula (I) may be bonded to any one of the positions1–8 of the azulene ring.

The compound of the present invention includes a mixture or isolatedproduct of various stereoisomers such as a tautomer and an opticalisomer.

The compound of the present invention may form an acid-addition salt or,depending on the type of substituent, a salt with a base. Specificexamples of such a salt include aid-addition salt with a mineral acidsuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, nitric acid, and phosphoric acid; an organic acid such as formicacid, acetic acid, propionic acid, oxalic acid, malonic acid, succinicacid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid,citric acid, methanesulfonic acid, and ethanesulfonic acid; an acidicamino acid such as aspartic acid and glutamic acid; a salt of aninorganic base such as sodium, potassium, magnesium, calcium, andaluminum; an organic base such as methylamine, ethylamine, andethanolamine; a basic amino acid such as lysine and ornithine; andammonium salts.

The compound of the present invention further includes hydrates andvarious pharmaceutically acceptable solvates and polymorphs.

The compound of the present invention should not be limited to thecompounds later described in examples, but includes all the compounds ofthe above formula (I) (azulene derivatives) and the pharmaceuticallyacceptable salts thereof.

Moreover, the compound of the present invention may includes any prodrugwhich is converted to any one of compounds of the above formula (I) orsalts thereof in the body as a result of the metabolism in the body. Asa group for forming the prodrug of the compound of the presentinvention, a group described in Prog. Med. 5: 2157–2161 (1985) or agroup described in “Development of Pharmaceuticals,” vol. 7, MolecularDesign, 163–198 (Hirokawa Shoten, 1990) can be given. Therefore, thewhole contents of those literatures are incorporated herein byreference.

The compound of the present invention or the pharmaceutically acceptablesalt thereof can be produced by various known synthesizing methodsutilizing characteristics based on the type of its basic structure orsubstituent. In this case, from the viewpoint of production technique,it may be effective to replace the functional group with a suitableprotective group, specifically, a group which can be readily convertedto the functional group, at the stage of a starting material orintermediate, depending on the type of functional group. Following this,the protective group is optionally removed to obtain the targetcompound. Examples of such a functional group include a hydroxyl groupand carboxyl group. Examples of the protective group for thesefunctional groups include protective groups described in Greene andWuts, “Protective Groups in Organic Synthesis,” Second Edition. Thesegroups may be suitably used according to the reaction conditions.

PREPARATION EXAMPLES

Typical production processes of the compound of the present inventionwill be described as follows.

Preparation Example 1

A process of Preparation Example 1 comprises subjecting an azulenecompound (1) to a Friedel-Crafts reaction followed by reduction toprepare a compound (2), reacting the compound (2) with a compound (3) byan addition reaction to prepare a compound (4), reducing the compound(4) to prepare a compound (I), and deprotecting the compound (I) toprepare a compound (I′), as shown in the following formula.

wherein R¹ to R¹² and A are the same as above.

The Friedel-Crafts reaction is carried out in the presence of anappropriate Lewis acid, in the absence of a solvent, or in anappropriate solvent. Specific examples of the Lewis acid includealuminum chloride, boron trichloride, zinc chloride, vanadium chloride,ferric chloride, and stannic chloride. Specific examples of the solventinclude ethers such as diethyl ether and tetrahydrofuran; haloalkylssuch as chloroform, dichloromethane, and 1,2-dichloroethane;dimethylformamide; dimethylsulfoxide; and a mixture of these solvents.The solvent is appropriately selected according to the type of reactionsubstrate or the reaction conditions. The reaction temperature is about20° C. to 180° C., and preferably about 20° C. to 40° C., while itvaries according to the type of starting material compounds, thereaction conditions, or the like within the above-mentioned rangethough.

The subsequent reduction reaction is carried out in the presence of anappropriate reducing agent and acid catalyst in a suitable solvent.Specific examples of the reducing agent include sodium borohydride,sodium cyanoborohydride, and lithium aluminum hydride. Specific examplesof the acid include boron trifluoride-diethyl ether complex,trifluoroacetic acid, and trifluoromethanesulfonic acid. Specificexamples of the solvent include ethers such as diethyl ether,tetrahydrofuran, and diglyme; haloalkyls such as chloroform,dichloromethane, and 1,2-dichloroethane; and a mixture of thesesolvents. The solvent is appropriately selected according to the type ofreaction substrate or the reaction conditions. The reaction temperatureis about 0° C. to 180° C., and preferably about 0° C. to 60° C., whileit varies according to the type of starting material compounds, thereaction conditions, or the like within the above-mentioned rangethough.

The subsequent addition reaction of the compound (2) to the compound (3)is carried out in the presence of an alkyl lithium reagent such asn-butyl lithium, sec-butyl lithium, or t-butyl lithium in a suitablesolvent. Specific examples of the solvent include ethers such as diethylether, tetrahydrofuran, and diglyme. The solvent is appropriatelyselected according to the type of reaction substrate or the reactionconditions. The reaction temperature is about −100° C. to 180° C., andpreferably about −80° C. to 30° C., while it varies according to thetype of starting material compounds, the reaction conditions, or thelike within the above-mentioned range though. The compound (4) may alsobe prepared by reacting the compound (2) with a Grignard reagentprepared using a metal reagent such as magnesium in a suitable solvent.Specific examples of the solvent include ethers such as diethyl ether,tetrahydrofuran, and diglyme. The solvent is appropriately selectedaccording to the type of reaction substrate or the reaction conditions.The reaction temperature is about 20° C. to 180° C., and preferablyabout 20° C. to 80° C., while it varies according to the type ofstarting material compounds, the reaction conditions, or the likethough.

The subsequent reduction reaction is carried out in the presence of anappropriate reducing agent and acid catalyst in a suitable solvent.Specific examples of the reducing agent include triethylsilane,triisopropylsilane, and t-butyldimethylsilane. Specific examples of theacid catalyst include boron trifluoride-diethyl ether complex,trifluoroacetic acid, and trimethylsilyl trifluoromethanesulfonate.Specific examples of the solvent include haloalkyls such as chloroform,dichloromethane, and 1,2-dichloroethane; ethers such as diethyl ether,tetrahydrofuran, and diglyme; acetonitrile; and a mixture of thesesolvents. The solvent is appropriately selected according to the type ofreaction substrate or the reaction conditions. The reaction temperatureis about −100° C. to 180° C., and preferably about −40° C. to 20° C.,while it varies according to the type of starting material compounds,the reaction conditions, or the like within the above-mentioned rangethough.

The deprotection is carried out in the presence of a metal catalyst suchas palladium/carbon, palladium hydroxide, or platinum/carbon in asuitable solvent in a hydrogen atmosphere, or in the presence of a Lewisacid in a suitable solvent. Specific examples of the Lewis acid includeboron trichloride, boron tribromide, and aluminum trichloride. Specificexamples of the solvent include ethers such as tetrahydrofuran anddioxane; esters such as ethyl acetate; alcohols such as methanol andethanol; acetonitrile; and a mixture of these solvents. The solvent isappropriately selected according to the type of reaction substrate orthe reaction conditions. The reaction temperature is about −100° C. to180° C., and preferably about −80° C. to 30° C., while it variesaccording to the type of starting material compounds, the reactionconditions, or the like within the above-mentioned range though.

Preparation Example 2

A process of Preparation Example 2 comprises reacting a compound (3)with a compound (5) to prepare a compound (6), reducing the compound (6)to prepare a compound (7), halogenating the compound (7) to prepare acompound (7′), reacting the compound (7′) with an azulene derivative (8)to prepare a compound (I), and deprotecting the compound (I) to preparea compound (I′), as shown in the following scheme.

wherein X represents a halogen, B(OR¹³)₃, wherein R¹³ is H or a loweralkyl, or SnR¹⁴ ₃, wherein R¹⁴ is a lower alkyl.

The reaction of the compound (3) with the compound (5) is carried out inthe same manner as in the reaction of the compound (2) with the compound(3) of Preparation Example 1.

The subsequent reduction reaction to prepare the compound (7) is carriedout in the same manner as in the reduction reaction of the compound (4)of Preparation Example 1. The subsequent halogenation of the compound(7) to prepare the compound (7′) is carried out in the presence of anappropriate halogenating agent in a suitable solvent. Specific examplesof the halogenating agent include N-bromosuccinimide, bromine, hydrogenbromide. Specific examples of the solvent include haloalkyls such asmethylene chloride, chloroform, and carbon tetrachloride; esters such asethyl acetate; ethers such as tetrahydrofuran and dioxane;dimethylsulfoxide; acetic acid; water; and a mixture of these solvents.The solvent is appropriately selected according to the type of reactionsubstrate or the reaction conditions. The reaction temperature is about−100° C. to 180° C., and preferably about 0° C. to 100° C., while itvaries according to the type of starting material compounds, thereaction conditions, or the like within the above-mentioned rangethough.

The subsequent reaction of the compound (7′) with the compound (8) iscarried out in the presence of an appropriate palladium catalyst or inthe presence of an appropriate palladium catalyst and an appropriatephosphine in a suitable solvent. Specific examples of the catalystinclude tetrakistriphenylphosphine palladium(0), palladium acetate,bistriphenylphosphine dichloropalladium(II),1,2-bis(diphenylphosphinoethane)dichloropalladium(II),1,1′-bis(diphenylphosphinoferrocene)dichloropalladium(II), andtris(dibenzylideneacetone)dipalladium(0). Specific examples of thephosphine include trifurylphosphine, 2-(dicyclohexylphosphino)biphenyl,and tri(t-butyl)phosphine. Specific examples of the solvent includeethers such as diethyl ether, tetrahydrofuran, dioxane, and diglyme;alcohols such as methanol, ethanol, and isopropanol; benzene; toluene;water; and a mixture of these solvents. The solvent is appropriatelyselected according to the type of reaction substrate or the reactionconditions. The reaction temperature is about −100° C. to 180° C., andpreferably about 0° C. to 100° C., while it varies according to the typeof starting material compounds, the reaction conditions, or the likewithin the above-mentioned range though.

This reaction may be carried out by reacting the compound (7′) with ametal in a suitable solvent to prepare a metal reagent, and thenreacting the reagent with the compound (8) in the presence of apalladium catalyst. Specific examples of the metal include copper, zinc,iron, and magnesium. The palladium catalyst, solvent, and reactiontemperature are the same as above.

The deprotection is carried out in the presence of an appropriate basein a suitable solvent. Specific examples of the base include sodiumhydroxide, potassium hydroxide, sodium methoxide, and sodium ethoxide.Specific examples of the solvent include ethers such as tetrahydrofuran,dioxane, and diglyme; alcohols such as methanol, ethanol, andisopropanol; acetonitrile; water; and a mixture of these solvents. Thesolvent is appropriately selected according to the type of reactionsubstrate or the reaction conditions. The reaction temperature is about−100° C. to 180° C., and preferably about 0° C. to 100° C., while itvaries according to the type of starting material compounds, thereaction conditions, or the like within the above-mentioned rangethough.

The deprotection is also carried out in the presence of an appropriateLewis acid in a suitable solvent. Specific examples of the Lewis acidinclude boron trichloride, boron tribromide, and aluminum trichloride.Specific examples of the solvent include ethers such as tetrahydrofuranand dioxane; esters such as ethyl acetate; alcohols such as methanol andethanol; acetonitrile; and a mixture of these solvents. The solvent isappropriately selected according to the type of reaction substrate orthe reaction conditions. The reaction temperature is about −100° C. to180° C., and preferably about −80° C. to 60° C., while it variesaccording to the type of starting material compounds, the reactionconditions, or the like within the above-mentioned range though.

Preparation Example 3

A process of Preparation Example 3 comprises protecting an alcoholderivative (9), reacting the protected derivative (9) with a compound(3) to prepare a compound (10), reducing and deprotecting the compound(10) to prepare a compound (11), halogenating the compound (11) toprepare a compound (7′), reacting the compound (7′) with an azulenederivative (8) to prepare a compound (I), and deprotecting the compound(I) to prepare a compound (I′), as shown in the following scheme.

wherein P represents a protective group, and X represents a halogen,B(R¹³)₃, wherein R¹³ is H or a lower alkyl, or SnR¹⁴ ₃, wherein R¹⁴ is alower alkyl.

The alcohol derivative (9) is protected by a suitable protective groupsuch as a t-butyldimethylsilyl group, t-butyldiphenylsilyl group, andtetrahydropyranyl group according to a conventional method. Thesubsequent reaction with the compound (3) is carried out in the samemanner as in the reaction of the compound (2) with the compound (3) ofPreparation Example 1.

The subsequent reduction reaction is carried out in the same manner asin the reduction reaction of the compound (4) of Preparation Example 1.The subsequent deprotection is carried out in the presence of anappropriate catalyst in a suitable solvent. Specific examples of thecatalyst include tetrabutylammonium fluoride, boron trifluoride-diethylether complex, hydrogen fluoride, acetic acid, and p-toluenesulfonicacid. Specific examples of the solvent include ethers such astetrahydrofuran and dioxane; alcohols such as methanol and ethanol;water; and a mixture of these solvents. The solvent is appropriatelyselected according to the type of reaction substrate or the reactionconditions. The reaction temperature is about −100° C. to 180° C., andpreferably about 20° C. to 80° C., while it varies according to the typeof starting material compounds, the reaction conditions, or the likewithin the above-mentioned range though.

The subsequent halogenation is carried out in the presence of ahalogenating agent and triphenyl phosphine in a suitable solvent.Specific examples of the halogenating agent include N-bromosuccinmide,bromine, carbon tetrabromide, and copper (II) bromide. Specific examplesof the solvent include haloalkyls such as methylene chloride,chloroform, and carbon tetrachloride; esters such as ethyl acetate;ethers such as tetrahydrofuran and dioxane; benzene; toluene;dimethylsulfoxide; acetic acid; water; and a mixture of these solvents.The solvent is appropriately selected according to the type of reactionsubstrate or the reaction conditions. The reaction temperature is about−100° C. to 180° C., and preferably about 0° C. to 100° C., while itvaries according to the type of starting material compounds, thereaction conditions, or the like within the above-mentioned rangethough.

The subsequent reaction of the compound (7′) with the compound (8) andthe deprotection are carried out in the same manner as in PreparationExample 2.

Preparation Example 4

A process of Preparation Example 4 comprises reacting a bromobenzenederivative (12) with a compound (3) to prepare a compound (13), reducingthe compound (13) to prepare a compound (14), converting the compound(14) to a trialkyltin derivative (15), reacting the derivative (15) withan azulene derivative (16) to prepare a compound (I), and deprotectingthe compound (I) to prepare a compound (I′), as shown in the followingscheme.

wherein Y represents a halogen and R¹⁵ represents a lower alkyl.

The reaction of the bromobenzene derivative (12) with the compound (3)is carried out in the same manner as in the reaction of the compound (2)with the compound (3) of Preparation Example 1.

The subsequent reduction reaction is carried out in the same manner asin the reduction reaction of the compound (4) of Preparation Example 1.The subsequent conversion to the trialkyltin derivative is carried outin the presence of hexaalkylditin and an appropriate palladium catalystin a suitable solvent. Specific examples of the palladium catalystinclude tetrakistriphenylphosphine palladium(0), palladium acetate,bistriphenylphosphine dichloropalladium(II),1,2-bis(diphenylphosphinoethane)dichloropalladium(II), and1,1′-bis(diphenylphosphinoferrocene)dichloropalladium(II). Specificexamples of the solvent include ethers such as diethyl ether,tetrahydrofuran, dioxane, and diglyme; alcohols such as methanol,ethanol, and isopropanol; benzene; toluene; water; and a mixture ofthese solvents. The solvent is appropriately selected according to thetype of reaction substrate or the reaction conditions. The reactiontemperature is about −100° C. to 180° C., and preferably about 0° C. to100° C., while it varies according to the type of starting materialcompounds, the reaction conditions, or the like within theabove-mentioned range though.

The subsequent reaction with the azulene derivative (16) is carried outin the presence of an appropriate palladium catalyst or in the presenceof an appropriate palladium catalyst and an appropriate phosphine in asuitable solvent. Specific examples of the catalyst includetetrakistriphenylphosphine palladium(0), palladium acetate,bistriphenylphosphine dichloropalladium(II),1,2-bis(diphenylphosphinoethane) dichloropalladium(II),1,1′-bis(diphenylphosphinoferrocene) dichloropalladium(II), andtris(dibenzylideneacetone) dipalladium(0). Specific examples of thephosphine include trifurylphosphine, 2-(dicyclohexylphosphino)biphenyl,and tri(t-butyl)phosphine. Specific examples of the solvent includeethers such as diethyl ether, tetrahydrofuran, dioxane, and diglyme;alcohols such as methanol, ethanol, and isopropanol; benzene; toluene;water; and a mixture of these solvents. The solvent is appropriatelyselected according to the type of reaction substrate or the reactionconditions. The reaction temperature is about −100° C. to 180° C., andpreferably about 0° C. to 100° C., while it varies according to the typeof starting material compounds, the reaction conditions, or the likewithin the above-mentioned range though. The deprotection is carried outin the same manner as in Preparation Example 2.

Preparation Example 5

A process of Preparation Example 5 comprises brominating a phenylaceticacid derivative (17) to prepare a compound (18), converting the compound(18) to a phenylacetone derivative (19), cyclizing the derivative (19)with a compound (20) to prepare a compound (2), reacting the compound(2) with a compound (3) to prepare a compound (4), reducing the compound(4) to prepare a compound (I), and deprotecting the compound (I) toprepare a compound (I′), as shown in the following scheme.

The bromination of the phenylacetic acid derivative (17) is carried outin the presence of an appropriate brominating agent in a suitablesolvent. Specific examples of the brominating agent includeN-bromosuccinimide, bromine, hydrogen bromide. Specific examples of thesolvent include haloalkyls such as methylene chloride, chloroform, andcarbon tetrachloride; esters such as ethyl acetate; ethers such astetrahydrofuran and dioxane; dimethylsulfoxide; acetic acid; water; anda mixture of these solvents. The solvent is appropriately selectedaccording to the type of reaction substrate or the reaction conditions.The reaction temperature is about −100° C. to 180° C., and preferablyabout 0° C. to 100° C., while it varies according to the type ofstarting material compounds, the reaction conditions, or the like withinthe above-mentioned range though.

The subsequent derivation to the phenylacetone derivative (19) iscarried out in the presence of an appropriate base in a suitablesolvent. Specific examples of the base include sodium acetate, potassiumacetate, and pyridine. Specific examples of the solvent include aceticanhydride. The reaction temperature is about −100° C. to 180° C., andpreferably about 30° C. to 150° C., while it varies according to thetype of starting material compounds, the reaction conditions, or thelike within the above-mentioned range though.

The subsequent cyclization reaction is carried out by reacting thecompound (19) with a suitable amine in the presence of an appropriatedehydrating agent in a suitable solvent and then reacting the mixturewith the compound (20) in a suitable solvent. Specific examples of theamine include morpholine, pyrrolidine, N-methylpiperazine, diethylamine,diisopropylamine. Specific examples of the dehydrating agent includemagnesium sulfate and sodium sulfate. Specific examples of the solventinclude ethers such as tetrahydrofuran, dioxane, and diethyl ether;haloalkyls such as methylene chloride, chloroform, and carbontetrachloride; esters such as ethyl acetate; alcohols such as methanol,ethanol, and isopropanol; benzene; toluene; acetonitrile; water; and amixture of these solvents. The solvent is appropriately selectedaccording to the type of reaction substrate or the reaction conditions.The reaction temperature is about −100° C. to 180° C., and preferablyabout 20° C. to 120° C., while it varies according to the type ofstarting material compounds, the reaction conditions, or the like withinthe above-mentioned range though.

The subsequent addition reaction to the compound (3) and the reductionare carried out in the same manner as in the addition reaction and thereduction of Preparation Example 1.

The deprotection is carried out in the same manner as in PreparationExample 2.

BEST MODE FOR CARRYING OUT THE INVENTION EXAMPLES

The compound of the present invention will now be described in moredetail by way of examples. Since starting material compounds of thecompound of the present invention include novel compounds, the methodsfor preparing these compounds will also be described in referenceexamples.

Reference Example 1

Aluminum chloride (1.87 g) was added to a solution of 1-methylazulene (2g) in methylene chloride (20 ml) at 0° C. and the mixture was stirredfor 15 minutes. Then, a solution of 3-bromobenzoyl chloride (1.86 ml) inmethylene chloride (5 ml) was added dropwise to the reaction mixture at0° C. and the mixture was stirred for one hour. The reaction mixture wasadded to 10% aqueous solution of hydrochloric acid under cooling withice and was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated. The residue was purified bysilica gel column chromatography (n-hexane-ethyl acetate) to obtain(3-bromophenyl)(3-methylazulen-1-yl)methanone (1.2 g).

Reference Example 2

Boron trifluoride-diethyl ether complex (1.17 ml) was added to asolution of (3-bromophenyl)(1-methylazulen-2-yl) methanone (0.5 g) indiglyme-ether (ratio: 1:1, 2.0 ml) at 0° C. and the mixture was stirredfor 20 minutes. Then, sodium borohydride (0.68 g) was added to thereaction mixture and the mixture was stirred at room temperature for onehour. The reaction mixture was added to ice-cooled water and extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried over anhydrous sodium sulfate. After filtration, the filtratewas concentrated. The residue was purified by silica gel columnchromatography (n-hexane-ether) to obtain1-(3-bromobenzyl)-3-methylazulene (0.21 g).

Reference Example 3

A 1.6 M hexane solution of n-butyl lithium (2.44 ml) was added dropwiseto a solution of 2-(3-bromobenzyl)-1-methylazulene (1.2 g) in THF (8.0ml) at −78° C. and the mixture was stirred for one hour. Then, asolution of 2,3,4,6-tetra-O-benzyl-D-(+)-glucono-1,5-lactone (2.08 g) inTHF (8.0 ml) was added dropwise to the reaction mixture and the mixturewas stirred for one hour. Saturated aqueous solution of ammoniumchloride was added to the reaction mixture and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried over anhydrous sodium sulfate. After filtration, the filtratewas concentrated. The residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate) to obtain2,3,4,6-tetra-O-benzyl-1-C-[3-[(3-methylazulen-1-yl)methyl]phenyl]-D-glucopyranose(1.74 g).

The compounds of Reference Examples 4, 5, and 6 were obtainedrespectively in the same manner as in Reference Examples 1, 2, and 3.

Reference Example 7

A 1.6 M hexane solution of n-butyl lithium (11 ml) was added dropwise toa solution of 3-bromo-4-ethoxytoluene (3.6 g) in THF (50 ml) at −78° C.and the mixture was stirred for 15 minutes. Then, a solution of2,3,4,6-tetra-O-benzyl-D-(+)-glucono-1,5-lactone (7.6 g) in THF (10 ml)was added dropwise to the reaction mixture and the mixture was stirredfor 2.5 hours. Saturated aqueous solution of ammonium chloride was addedto the reaction mixture and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated. The resulting precipitates were collected by filtration toobtain2,3,4,6-tetra-O-benzyl-1-C-(2-ethoxy-5-methylphenyl)-D-glucopyranose(3.53 g).

Reference Example 8

Boron trifluoride-diethyl ether complex (0.6 ml) and triethylsilane (1.7ml) were added dropwise to a solution of2,3,4,6-tetra-O-benzyl-1-C-(2-ethoxy-5-methylphenyl)-D-glucopyranose(3.5 g) at −50° C. and the mixture was stirred for two hours. Saturatedaqueous solution of potassium carbonate was added to the reactionmixture and the mixture was extracted with chloroform. The organic layerwas washed with saturated brine and dried over anhydrous sodium sulfate.After filtration, the filtrate was concentrated. The residue waspurified by silica gel column chromatography (hexane-ethyl acetate) toobtain(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-(2-ethoxy-5-methylphenyl)-D-glucitol(3.4 g).

Reference Example 9

A 1.0 M methylene chloride solution (31.0 ml) of boron trichloride wasadded dropwise to a solution of(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-(2-ethoxy-5-methylphenyl)-D-glucitol(3.4 g) in methylene chloride (50 ml) at −78° C. and the mixture wasstirred for 30 minutes. Methanol (10 ml) was added to the reactionmixture and the mixture was stirred for 10 minutes and concentrated. Theresidue was dissolved in pyridine (20 ml) and acetic anhydride (10 ml)was added to the solution, followed by stirring for 12 hours at roomtemperature. The reaction mixture was diluted with ethyl acetate. Thediluted product was washed with 10% aqueous solution of hydrochloricacid, saturated aqueous solution of sodium hydrogencarbonate, andsaturated brine in that order and dried over anhydrous sodium sulfate.After filtration, the filtrate was concentrated. The residue waspurified by silica gel column chromatography (n-hexane-ethyl acetate) toobtain(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(2-ethoxy-5-methylphenyl)-D-glucitol(1.3 g).

Reference Example 10

N-bromosuccinimide (1.7 g) and benzoyl peroxide (0.1 g) were added to asolution of(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(2-ethoxy-5-methylphenyl)-D-glucitol(3.7 g) in carbon tetrachloride (30.0 ml) and the mixture was refluxedwith heating for one hour. The reaction mixture was diluted withchloroform and the diluted product was washed with saturated aqueoussolution of sodium hydrogencarbonate, saturated aqueous solution ofsodium thiosulfate, and saturated brine in that order and dried overanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated. The resulting precipitates were collected by filtration toobtain(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[5-(bromomethyl)-2-ethoxyphenyl]-D-glucitol(1.4 g).

Reference Example 11

A catalytic amount of iodine was added to a suspension of metalmagnesium (0.22 g) in THF (5.0 ml) in an argon atmosphere. Then, asolution of the compound in THF (5.0 ml) was added dropwise to themixture, followed by refluxing with heating for one hour. The Grignardreagent thus prepared was added dropwise to a solution of3-bromo-4-methylbenzaldehyde dimethylacetal (2.45 g) in THF (5.0 ml) at0° C. and the mixture was stirred for one hour. An aqueous solution ofammonium chloride was added to the reaction mixture and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated. The residue was purified bysilica gel column chromatography (n-hexane-ethyl acetate) to obtain2,3,4,6-tetra-O-benzyl-1-C-[5-(dimethoxymethyl)-2-methylphenyl]-D-glucopyranose(2.4 g).

Reference Example 12

Sulfamic acid (0.4 g) and sodium chlorite (0.4 g) were added dropwise toa solution of2,3,4,6-tetra-O-benzyl-1-C-[5-(dimethoxymethyl)-2-methylphenyl]-D-glucopyranose(2.4 g) in acetone-water (ratio: 5:1, 12 ml) at room temperature and themixture was stirred for three hours. Acetone was evaporated from thereaction mixture and water was added. The mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine in that order and dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated to obtain4-methyl-3-[(3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]-2-hydroxytetrahydro-2H-pyran-2-yl]benzoicacid (1.5 g).

The compound of Reference Example 13 was obtained in the same manner asin Reference Example 8.

Reference Example 14

Methyl iodide (0.17 ml) and potassium carbonate (0.4 g) were added to asolution of4-methyl-3-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]-tetrahydro-2H-pyran-2-yl]benzoicacid (1.5 g) in DMF (10 ml) at room temperature and the mixture wasstirred for three hours. The insoluble matter was separated byfiltration and the filtrate was diluted with ethyl acetate. The dilutedsolution was washed with water and saturated brine in that order anddried over anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate) to obtain methyl4-methyl-3-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]-tetrahydro-2H-pyran-2-yl]benzoate(1.3 g).

Reference Example 15

Lithium aluminum hydride (73 mg) was added to a solution of methyl4-methyl-3-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl]benzoate(1.3 g) in THF (10 ml) at 0° C. and the mixture was stirred for onehour. The reaction mixture was poured into ice-cooled water and theinsoluble matter was separated by filtration. The filtrate was extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried over anhydrous sodium sulfate. After filtration, the filtratewas concentrated. The residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate) to obtain(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[5-(hydroxymethyl)-2-methylphenyl]-D-glucitol(1.0 g).

Reference Example 16

Carbon tetrabromide (0.62 g) and triphenylphosphine (0.49 g) were addedto a solution of(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[5-(hydroxymethyl)-2-methylphenyl]-D-glucitol(1.0 g) in methylene chloride (10 ml) at room temperature and themixture was stirred for one hour. The reaction mixture was concentratedand the residue was purified by silica gel column chromatography(n-hexane-ethyl acetate) to obtain(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[5-(bromomethyl)-2-methylphenyl]-D-glucitol(0.8 g).

The compounds of Reference Examples 17 and 18 were obtained respectivelyin the same manner as in Reference Examples 1 and 2.

Reference Example 19

A 1.6 M n-hexane solution of n-butyl lithium (14.0 ml) was addeddropwise to a solution of(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[3-bromo-5-(methoxymethyl)phenyl]-D-glucitol(7.8 g) in THF (5.0 ml) at −78° C. and the mixture was stirred for 30minutes. DMF (1.0 ml) was added dropwise to the reaction mixture and themixture was stirred for four hours. Saturated aqueous solution ofammonium chloride was added to the reaction mixture and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated. The residue was purified bysilica gel column chromatography (n-hexane-ethyl acetate) to obtainmethyl3-methoxymethyl-5-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]-tetrahydro-2H-pyran-2-yl]benzaldehyde(2.6 g).

Reference Example 20

Sodium borohydride (0.15 g) was added to a solution of3-methoxymethyl-5-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl]benzaldehyde(2.6 g) in a 1:1 mixture of methanol and THF (10 ml) and the mixture wasstirred for one hour. Acetone (5.0 ml) was added to the reaction mixtureand the mixture was stirred for 10 minutes. Water was added to thereaction mixture and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydroussodium sulfate. After filtration, the filtrate was concentrated. Theresidue was purified by silica gel column chromatography (n-hexane-ethylacetate) to obtain(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[3-(hydroxymethyl)-5-(methoxymethyl)phenyl]-D-glucitol (2.1 g).

The compounds of Reference Examples 21, 22, and 23 were obtainedrespectively in the same manner as in Reference Examples 6, 11, andExample 1.

Reference Example 24

A 1.0 M THF solution of tetrabutylammonium fluoride (3.8 ml) was addedto a solution of(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[3-([[t-butyl(diphenyl)silyl]oxy]methyl)phenyl]-D-glucitol (1.7 g) in THF (10.0 ml) at room temperature and themixture was stirred for two hours. 10% aqueous solution of sodiumhydroxide (3.0 ml) was further added to the reaction mixture and themixture was refluxed with stirring for one hour. Water was added to thereaction mixture and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydroussodium sulfate. After filtration, the filtrate was concentrated. Theresidue was purified by silica gel column chromatography (n-hexane-ethylacetate) to obtain(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[3-(hydroxymethyl)phenyl]-D-glucitol(0.7 g).

The compound of Reference Example 25 was obtained in the same manner asin Reference Example 16.

Reference Example 26

Imidazole (3.45 g) and t-butyldimethylchlorosilane (17.6 g) were addedto a solution of 5-bromo-2-methoxybenzyl alcohol (10.0 g) in DMF (100ml) under cooling with ice and the mixture was stirred for two hours.The reaction mixture was added to ice-cooled water and extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate) to obtain[(5-bromo-2-methoxybenzyl)oxy](t-butyl)dimethylsilane (15.2 g).

The compounds of Reference Examples 27, 28, 29, 30, and 31 were obtainedrespectively in the same manner as in Reference Example 3, Example 1,Reference Example 16, Reference Example 11, and Example 1.

Reference Example 32

Hexabutylditin (10.0 g) and tetrakistriphenylphosphine palladium (0)(0.24 g) were added to a solution of(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-(3-bromophenyl)-D-glucitol(5.0 g) in toluene (8.0 ml) in an argon atmosphere and the mixture wasrefluxed with stirring for 17 hours. The reaction mixture wasconcentrated. The residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate) to obtain(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[3-(tributylstanyl)phenyl]-D-glucitol(4.0 g).

Reference Example 33

Manganese dioxide (20.4 g) was added to a solution of(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[3-(hydroxymethyl)phenyl]-D-glucitol(6.8 g) obtained in Reference Example 24 in chloroform (100 ml) and themixture was refluxed with stirring for 1.5 hours. After separating theinsoluble matter from the reaction mixture by filtration through celiteat room temperature, the filtrate was concentrated. The residue waspurified by silica gel column chromatography (n-hexane-ethyl acetate) toobtain3-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl]benzaldehyde(6.8 g).

Reference Example 34

Potassium t-butoxide (3.6 g) was added to a solution ofmethyltriphenylphosphonium bromide (11.6 g) in THF (100 ml) at roomtemperature and the mixture was stirred for 10 minutes. A solution of3-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl]benzaldehyde(6.8 g) in THF (10 ml) was added dropwise and the mixture was stirredfor one hour at room temperature. Saturated aqueous solution of ammoniumchloride was added to the reaction mixture and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried over anhydrous sodium sulfate. After filtration, the filtratewas concentrated. The residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate) to obtain(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-(3-vinylphenyl)-D-glucitol(6.8 g).

The compounds of Reference Examples 35, 36, 37, 38, 39, and 40 wereobtained respectively in the same manner as in Reference Example 26,Reference Example 3, Example 1, Reference Example 16, Reference Example3, and Example 1.

Reference Example 41

5% palladium/carbon (1.0 g) was added to a solution of(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-(3-bromo-5-methoxyphenyl)-D-glucitol(10.0 g) in THF-methanol (ratio: 1:1, 100 ml). Two drops of a 1 Maqueous solution of hydrochloric acid was further added to the mixture,followed by stirring for 30 minutes in a hydrogen atmosphere. Afterfiltrating the reaction mixture, the filtrate was concentrated. Theresidue was purified by silica gel column chromatography(chloroform-methanol) to obtain(1S)-1,5-anhydro-1-(3-bromo-5-methoxyphenyl)-D-glucitol (2.9 g).

The compounds of Reference Examples 42, 43, 44, 45, and 46 were obtainedrespectively in the same manner as in Example 37, Reference Example 32,Reference Example 41, Example 37, and Reference Example 32.

Reference Example 47

1-bromo-2,4-dimethoxybenzene (9.1 ml) was added to a solution of2,3,4,6-tetra-O-benzyl-1-O-(trifluoroacetyl)-α-D-glucopyranose (20.0 g)in methylene chloride (100 ml) and the mixture was stirred for 10minutes. Boron trifluoride-diethyl ether complex (3.9 ml) was added tothe reaction mixture and the mixture was stirred at room temperature for12 hours. Water was added to the reaction mixture and the mixture wasextracted with methylene chloride. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated. The residue was purified bysilica gel column chromatography (n-hexane-ethyl acetate) to obtain(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-(5-bromo-2,4-dimethoxyphenyl)-D-glucitol(17.0 g).

The compound of Reference Example 48 was obtained in the same manner asin Reference Example 41.

Reference Example 49

Diisopropylethylamine (2.98 g) and chloromethyl methyl ether (1.3 ml)were added to a solution of(1S)-1,5-anhydro-1-(5-bromo-2,4-dimethoxyphenyl)-D-glucitol (1.35 g) inmethylene chloride (15 ml) at 0° C. and the mixture was stirred at roomtemperature for 12 hours. The reaction mixture was added to ice-cooledwater and extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated. The residue was purified bysilica gel column chromatography (n-hexane-ethyl acetate) to obtain(1S)-1,5-anhydro-1-(5-bromo-2,4-dimethoxyphenyl)-2,3,4,6-tetrakis-O-(methoxymethyl)-D-glucitol(0.7 g).

The compound of Reference Example 50 was obtained in the same manner asin Reference Example 32.

Reference Example 51

Sodium borohydride (0.26 g) was added to a solution of6-isopropylazulene-2-carboaldehyde (1.4 g) in methanol (30 ml) at 0° C.and the mixture was stirred for one hour. Acetone was added to thereaction mixture and the mixture was stirred for 15 minutes. Thereaction mixture was concentrated. The residue was purified by silicagel column chromatography (n-hexane-ethyl acetate) to obtain(6-isopropylazulen-2-yl)methanol (1.15 g).

Reference Example 52

Triphenylphosphine (0.66 g) was added to a solution of(6-isopropylazulen-2-yl)methanol (0.5 g) in carbon tetrachloride (10.0ml) and the mixture was refluxed with heating for 15 hours. The reactionmixture was concentrated. The residue was purified by silica gel columnchromatography (n-hexane-diethyl ether) to obtain2-(chloromethyl)-6-isopropylazulene (0.38 g).

The compound of Reference Example 53 was obtained in the same manner asin Reference Example 52.

Reference Example 54

[1,2-bis(diphenylphosphino)ethane]dichloropalladium (II) (1.48 g) wasadded to a solution of methyl 2-chloroazulene-1-carboxylate (11.38 g)and hexamethylditin (35.9 g) in 1,4-dioxane (272 ml) at room temperatureand the mixture was heated to 60° C. and stirred for 38 hours. Afterevaporating the solvent under reduced pressure, the resulting residuewas purified by silica gel column chromatography (hexane-ether acetate)to obtain methyl 2-(tributylstanyl)azulene-1-carboxylate (12.36 g).

Reference Example 55

A 1.0 M dichloromethane solution of tin tetrachloride (16.5 ml) wasadded to a suspension of 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose(6.41 g), 1,2-diethoxy-4-methylbenzene (2.47 g), and silvertrifluoroacetate (3.63 g) in 1,2-dichloroethane (70 ml) at 0° C. and themixture was stirred at the same temperature for one hour. After heatingto room temperature and stirring for 15 hours, saturated aqueoussolution of sodium bicarbonate was added to the mixture. The reactionmixture was filtered through celite and the filtrate was extracted withchloroform. The organic layer was washed with water and saturated brineand dried over anhydrous sodium sulfate. After filtration, the solventwas evaporated under reduced pressure. Methanol (200 ml) and a catalyticamount of sodium methoxide were added to the resulting residue and themixture was stirred at room temperature overnight. The solvent wasevaporated under reduced pressure and the resulting residue was purifiedby silica gel column chromatography (chloroform-methanol). Pyridine (30ml), acetic anhydride (5 ml), and a catalytic amount of4-dimethylaminopyridine were added to the resulting residue and themixture was stirred at room temperature for two days. Toluene was addedto the reaction mixture and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate-n-hexane) to obtain(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(2,3-diethoxy-5-methylphenyl)-D-glucitol(2.51 g).

Reference Example 56

A suspension of(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(2,3-diethoxy-5-methylphenyl)-D-glucitol(500 mg) and N-bromosuccinimide (209 mg) in carbon tetrachloride (10 ml)was refluxed with heating and 2,2′-azobis(isobutyronitrile) (80 mg) wasadded. The mixture was stirred for 30 minutes under refluxing and thereaction mixture was allowed to be cooled to room temperature. Afterevaporating the solvent under reduced pressure, the resulting residuewas purified by silica gel column chromatography (ethylacetate-n-hexane) to obtain(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[5-(bromomethyl)-2,3-diethoxyphenyl]-D-glucitol(464 mg).

The compounds of Reference Examples 57 and 58 were obtained respectivelyin the same manner as in Reference Examples 55 and 56.

Reference Example 59

A 1.56 M n-hexane solution of n-butyl lithium (3.57 ml) and2-fluorotoluene (0.66 ml) were added in that order to a suspension ofpotassium t-butoxide (625 mg) in THF (11 ml) at −78° C. and the mixturewas stirred at the same temperature for 1.5 hours. A solution of2,3,4,6-tetra-O-benzyl-D-(+)-glucono-1,5-lactone (3.00 g) in THF (10 ml)was added dropwise to the reaction mixture and the mixture was stirredat the same temperature for 30 minutes. After the addition of a 1 Maqueous solution of hydrochloric acid, the mixture was heated to roomtemperature. The reaction mixture was extracted with diethyl ether. Theorganic layer was washed with saturated brine and dried over anhydroussodium sulfate. After filtration, the solvent was evaporated underreduced pressure. The filtrate was concentrated and dried to be solid.The resulting residue was dissolved in dichloroethane (5 ml) andacetonitrile (25 ml). Triisopropylsilane (2.27 ml) and borontrifluoride-diethyl ether complex (0.85 ml) were added to the solutionat −30° C. After stirring at the same temperature for 30 minutes,saturated aqueous solution of sodium bicarbonate was added to thereaction mixture. The mixture was extracted with diethyl ether. Theorganic layer was washed with saturated brine and dried over anhydroussodium sulfate. After filtration, the solvent was evaporated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (ethyl acetate-n-hexane) to obtain(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-(2-fluoro-3-methylphenyl)-D-glucitol(559 mg).

Reference Example 60

A suspension of(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-(2-fluoro-3-methylphenyl)-D-glucitol(550 mg) and 20% palladium hydroxide/carbon (300 mg) in THF (10ml)-methanol (5 ml) was stirred in a hydrogen atmosphere (1 atm) for 2.5days. The reaction mixture was filtered through celite and the filtratewas concentrated. Pyridine (5 ml), acetic anhydride (2 ml), and acatalytic amount of 4-dimethylaminopyridine were added to the resultingresidue and the mixture was stirred at room temperature for one hour.After evaporating the solvent under reduced pressure, the residue wasco-evaporated with toluene and dissolved in diethyl ether. This solutionwas washed with a 1 M aqueous solution of hydrochloric acid andsaturated brine and dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure toobtain(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(2-fluoro-3-methylphenyl)-D-glucitol(335 mg).

The compounds of Reference Examples 61, 62, 63, 64, and 65 were obtainedrespectively in the same manner as in Reference Examples 56, 55, 56, 55,and 56.

Reference Example 66

Sodium acetate (50.5 g) was added to a solution of3-bromo-4-hydroxyphenylacetic acid (28.5 g) in acetic anhydride (100 ml)and the mixture was refluxed with heating for 21 hours. After cooling toroom temperature, 20% aqueous solution of sodium hydroxide was added tothe reaction mixture to adjust to pH 11. The mixture was refluxed withheating for one hour. After cooling to room temperature, 10% aqueoussolution of hydrochloric acid was added to the reaction mixture toadjust to pH 6. The mixture was extracted with ethyl acetate. Theorganic layer was washed with water, saturated aqueous solution ofsodium bicarbonate, and saturated brine and dried over anhydrous sodiumsulfate. After filtration, the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate-n-hexane) to obtain 1-(3-bromo-4-hydroxyphenyl) acetone(22.2 g).

Reference Example 67

Potassium carbonate (2.7 g) and benzyl bromide (2.3 ml) were added to asolution of 1-(3-bromo-4-hydroxyphenyl) acetone (4.0 g) in DMF (40 ml)and the mixture was stirred at room temperature for six hours. Thereaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine and dried over anhydrous sodium sulfate. Afterfiltration, the solvent was evaporated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(ethyl acetate-n-hexane) to obtain1-[4-(benzyloxy)-3-bromophenyl]acetone (3.65 g).

Reference Example 68

Pyrrolidine (1.9 ml) and magnesium sulfate (2.74 g) were added to asolution of 1-[4-(benzyloxy)-3-bromophenyl]acetone (3.65 g) in diethylether (30 ml) and the mixture was stirred at room temperature for 12hours. After filtration, the solvent was evaporated under reducedpressure. The resulting residue was dried under reduced pressure anddissolved in ethanol (30 ml). 2H-cyclohepta[b]furan-2-on (0.5 g) wasadded to the solution and the mixture was refluxed with heating foreight hours. The reaction mixture was concentrated. The resultingresidue was purified by silica gel column chromatography (ethylacetate-n-hexane) to obtain 2-[4-(benzyloxy)-3-bromobenzyl]azulene (0.84g).

Reference Example 69

A 1.6 M n-hexane solution of n-butyl lithium (0.32 ml) was addeddropwise to a solution of 2-[4-(benzyloxy)-3-bromobenzyl]azulene (0.17g) in THF (3.0 ml) at −55° C. and the mixture was stirred at the sametemperature for 10 minutes. A solution of2,3,4,6-tetra-O-benzyl-glucono-1,5-lactone (0.12 g) in THF (3.0 ml) wasadded dropwise to the reaction mixture and the mixture was stirred atthe same temperature for 30 minutes. Saturated aqueous solution ofammonium chloride was added to the reaction mixture and the mixture wasextracted with ethyl acetate. The organic layer was washed with brineand dried over anhydrous sodium sulfate. After filtration, the solventwas evaporated under reduced pressure. The resulting residue waspurified by silica gel column chromatography (ethyl acetate-n-hexane) toobtain1-C-[5-(azulen-2-ylmethyl)-2-(benzyloxy)phenyl]-2,3,4,6-tetra-O-benzyl-D-glucopyranose(0.9 g).

Example 1

Boron trifluoride-diethyl ether complex (0.39 ml) and triisopropylsilane(1.23 ml) were added dropwise to a solution of2,3,4,6-tetra-O-benzyl-1-C-[3-[(3-methylazulen-1-yl)methyl]phenyl]-D-glucopyranose (2.3 g) in acetonitrile (40 ml) at −40°C. and the mixture was stirred for two hours. Saturated aqueous solutionof potassium carbonate was added to the reaction mixture and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated. The residue was purified bysilica gel column chromatography (n-hexane-ethyl acetate) to obtain(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[3-[(3-methylazulen-1-yl)methyl]phenyl]-D-glucitol (1.47 g).

Example 2

A 1 M n-heptane solution of boron tribromide (20 ml) was added dropwiseto a solution of(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[3-[(3-methylazulen-1-yl)methyl]phenyl]-D-glucitol(0.76 g) in methylene chloride (20 ml) at −78° C. and the mixture wasstirred for 30 minutes. Methylene chloride-toluene (ratio: 2:1, 60 ml)was added to the reaction mixture and methanol (6 ml) was further addedto the mixture. The reaction mixture was cooled to room temperature andconcentrated to the half amount, followed by adding methanol (25 ml) tothe mixture and concentrating. This operation was repeated three times.The residue prepared by the concentration was purified by silica gelcolumn chromatography (chloroform-methanol) to obtain(1S)-1,5-anhydro-1-[3-[(3-methylazulen-1-yl)methyl]phenyl]-D-glucitol(0.068 g).

The compounds of Examples 3 and 4 were obtained respectively in the samemanner as in Examples 1 and 2.

Example 5

Two drops of 1,2-dibromoethane was added to a suspension of zinc powder(0.17 g) in THF (5.0 ml) in an argon atmosphere and the mixture wasrefluxed with heating for five minutes. After cooling to roomtemperature, two drops of chlorotrimethylsilane was added to thereaction mixture. The mixture was stirred for 15 minutes. Next,(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[5-(bromomethyl)-2-ethoxyphenyl]-D-glucitol(1.4 g) was added to the reaction mixture and the mixture was refluxedwith heating for one hour. After cooling to room temperature,tetrakistriphenylphosphine palladium (0) (0.27 g) and methyl2-chloroazulene-1-carboxylate (0.28 g) were added to the reactionmixture. The mixture was refluxed with heating for six hours. Aftercooling to room temperature, the reaction mixture was poured into 10%aqueous solution of hydrochloric acid under cooling with ice. Themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated. The residue was purified bysilica gel column chromatography (n-hexane-ethyl acetate) to obtainmethyl2-(4-ethoxy-3-[(2S,3S,4R,5R,6R)-3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl]benzyl)azulene-1-carboxylate(0.58 g).

Example 6

10% aqueous solution of sodiumhydroxide (5.0 ml) was added dropwise to asolution of methyl2-(4-ethoxy-3-[(2S,3S,4R,5R,6R)-3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl]benzyl)azulene-1-carboxylate (0.58 g) inmethanol (5.0 ml) at room temperature. The mixture was stirred for 30minutes and refluxed with heating for further six hours. After coolingwith ice, the reaction mixture was neutralized by adding 10% aqueoussolution of hydrochloric acid. The neutralized product was extractedwith chloroform. The organic layer was washed with saturated brine anddried over anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (chloroform-methanol) to obtain2-(4-ethoxy-3-[(2S,3R,4R,5S,6R)-3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl]benzyl)azulene-1-carboxylicacid (0.4 g).

Example 7

p-Toluenesulfonic acid monohydrate (40 mg) was added to a suspension of2-(4-ethoxy-3-[(2S,3R,4R,5S,6R)-3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl]benzyl)azulene-1-carboxylicacid (0.36 g) inbenzene (10 ml) and the mixture was refluxed withheating for 15 minutes. The reaction mixture was concentrated. Theresidue was purified by silica gel column chromatography(chloroform-methanol) to obtain(1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-ethoxyphenyl]-D-glucitol(203 mg).

The compound of Example 8 was obtained in the same manner as in Example5.

Example 9

A 1.0 M methylene chloride solution of boron trichloride (3.0 ml) wasadded dropwise to a solution of methyl2-(4-methyl-3-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl]benzyl)azulene-1-carboxylate (0.39 g) in methylene chloride (10 ml) at −78° C.and the mixture was stirred for 15 minutes. Methanol (10 ml) was addedto the reaction mixture and the mixture was stirred for 10 minutes andconcentrated. The residue was purified by silica gel columnchromatography (chloroform-methanol) to obtain methyl2-(4-methyl-3-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]benzyl)azulene-1-carboxylate(0.08 g).

The compounds of Examples 10 and 11 were obtained respectively in thesame manner as in Examples 6 and 7.

Example 12

A 1.0 M methylene chloride solution of boron trichloride (3.0 ml) wasadded dropwise to a solution of methyl2-(4-methyl-3-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl]benzyl)azulene-1-carboxylate (0.39 g) in methylene chloride (10 ml) at −78° C.and the mixture was stirred for 15 minutes. Methanol (10.0 ml) was addedto the reaction mixture and the mixture was stirred for 10 minutes andconcentrated. The residue was purified by silica gel columnchromatography (chloroform-methanol) to obtain methyl3-benzyl-2-(4-methyl-3-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]benzyl)azulene-1-carboxylate(0.06 g).

The compounds of Examples 13, 14, 15, and 16 were obtained respectivelyin the same manner as in Examples 6, 7, 5, and 9.

Example 17

28% methanol solution of sodium methoxide (0.5 ml) was added to asolution of methyl2-[3-(chloromethyl)-5-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]benzyl]azulene-1-carboxylate (0.06 g) inmethanol (3.0 ml) at room temperature. The mixture was stirred for onehour. 10% aqueous solution of sodium hydroxide (3.0 ml) was furtheradded to the reaction mixture and the mixture was refluxed with heatingfor one hour. After cooling to room temperature, the reaction mixturewas neutralized by adding 10% aqueous solution of hydrochloric acid,extracted with chloroform. The organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate. After filtration, thefiltrate was concentrated. The residue was purified by silica gel columnchromatography (chloroform-methanol) to obtain(1S)-1,5-anhydro-1-[3-(azulen-2-ylmethyl)-5-(methoxymethyl)phenyl]-D-glucitol(0.02 g).

The compounds of Examples 18, 19, 20, 21, and 22 were obtainedrespectively in the same manner as in Examples 5, 9, 6, 7, and 5.

The compounds of Examples 23, 24, 25, 26, and 27 were obtainedrespectively in the same manner as in Examples 2, 6, 7, 5, and 6.

The compounds of Examples 28, 29, 30, 31, and 32 were obtainedrespectively in the same manner as in Examples 7, 5, 9, 6, and 7.

Example 33

Potassium carbonate (0.15 g) and bis (triphenylphosphine)dichloropalladium (II) (0.04 g) were added to a solution of(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[3-(tributylstanyl)phenyl]-D-glucitol(0.5 g) and methyl 2-chloroazulene-1-carboxylate (0.1 g) in 1,4-dioxane(3.0 ml) and the mixture was refluxed with heating for 15 hours. Thereaction mixture was concentrated. The residue was purified by silicagel column chromatography (n-hexane-ethyl acetate) to obtain methyl2-(3-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl]phenyl)azulene-1-carboxylate(0.25 g).

The compounds of Examples 34, 35, and 36 were obtained respectively inthe same manner as in Examples 2, 6, and 7.

Example 37

Acetic anhydride (0.3 ml) was added to a solution of(1S)-1,5-anhydro-1-[3-(azulen-2-ylmethyl)phenyl]-D-glucitol (0.24 g) inpyridine (5.0 ml) at room temperature and the mixture was stirred for 15hours. The reaction mixture was diluted with ethyl acetate. The dilutedsolution was washed with 10% aqueous solution of hydrochloric acid,saturated aqueous solution of sodium hydrogencarbonate, and saturatedbrine in that order and dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated. The residue was purified bysilica gel column chromatography (n-hexane-ethyl acetate) to obtain(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-(azulen-2-ylmethyl)phenyl]-D-glucitol(0.34 g).

Example 38

Aluminum chloride (0.24 g) was added to a solution of(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-(azulen-2-ylmethyl)phenyl]-D-glucitol(0.20 g) in methylene chloride (20 ml) at 0° C. and the mixture wasstirred for 30 minutes. Next, acetic anhydride (0.17 ml) was addeddropwise to the reaction mixture at 0° C. and the mixture was refluxedwith stirring for 30 minutes and further 16 hours. The reaction mixturewas added to 10% aqueous solution of hydrochloric acid under coolingwith ice and was extracted with ethyl acetate. The organic layer waswashed with saturated aqueous solution of sodium hydrogencarbonate andsaturated brine in that order and dried over anhydrous sodium sulfate.After filtration, the filtrate was concentrated. The residue waspurified by silica gel column chromatography (n-hexane-ethyl acetate) toobtain(2S,3S,4R,5R,6R)-2-[3-[(1-acetylazulen-2-yl)methyl]phenyl]-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-3,4,5-triyltriacetate (0.09 g).

Example 39

Sodium methoxide (16 mg) was added to a solution of(2S,3S,4R,5R,6R)-2-[3-[(1-acetylazulen-2-yl)methyl]phenyl]-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-3,4,5-triyltriacetate (0.09 g) in THF-methanol (ratio: 1:1, 6.0 ml) at 0° C. andthe mixture was stirred for two hours. After neutralizing with a cationexchange resin, the reaction mixture was added to 10% aqueous solutionof hydrochloric acid under cooling with ice. After filtration, thefiltrate was concentrated. The residue was purified by silica gel columnchromatography (chloroform-methanol) to obtain1-(2-[3-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]benzyl]azulen-1-yl)ethanone(0.06 g).

The compounds of Examples 40 and 41 were obtained respectively in thesame manner as in Reference Example 2 and Example 39.

Example 42

A THF solution (8.0 ml) of 9-borabicyclo[3.3.1]nonane was added to(1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-(3-vinylphenyl)-D-glucitol(1.0 g) and the mixture was refluxed with heating for four hours. Next,a 3 M aqueous solution of potassium phosphate (1.3 ml) and DMF (12 ml)were added to the reaction mixture. Methyl 2-chloroazulene-1-carboxylate(0.35 g) and 1,1′-diphenylphosphinoferrocene dichloropalladium (II)(0.12 g) were further added to the mixture, followed by stirring at 50°C. for two hours. After cooling to room temperature, the reactionmixture was poured into ice-cooled water and extracted with ethylacetate. The organic layer was washed with saturated aqueous solution ofsodium hydrogencarbonate and saturated brine in that order and driedover anhydrous sodium sulfate. The reaction mixture was concentrated.The residue was purified by silica gel column chromatography(n-hexane-ethyl acetate) to obtain methyl2-[2(3-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl]phenyl)ethyl]azulene-1-carboxylate(0.88 g).

The compounds of Examples 43, 44, 45, 46, 47, and 48 were obtainedrespectively in the same manner as in Examples 2, 6, 7, 5, 2, and 6.

The compounds of Examples 49, 50, 51, 52, 53, and 54 were obtainedrespectively in the same manner as in Examples 7, 33, 39, 2, 6, and 7.

The compounds of Examples 55, 56, 57, 58, and 59 were obtainedrespectively in the same manner as in Examples 33, 39, 33, 39, and 33.

Example 60

10% aqueous solution of hydrochloric acid (0.5 ml) was added to asolution of(1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2,4-dimethoxyphenyl]-2,3,4,6-tetrakis-O-(methoxymethyl)-D-glucitol(0.09 g) in methanol (2.0 ml) and the mixture was refluxed with heatingfor 30 minutes. The reaction mixture was poured into ice-cooled waterand extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated. The residue was purified bysilica gel column chromatography (chloroform-methanol) to obtain(1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2,4-dimethoxyphenyl]-D-glucitol(0.02 g).

Example 61

(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[4-(bromomethyl)-1-methoxy-2-naphthyl]-D-glucitol(0.62 g) was added to a suspension of methyl2-(tributylstanyl)azulene-1-carboxylate (0.25 g),tris(dibenzylideneacetone)dipalladium (0) (0.05 g),2-(dicyclohexylphosphino)biphenyl (0.05 g), potassium fluoride (0.09 g),and cesium carbonate (0.35 g) in 1,4-dioxane (20.0 ml). The mixture wasstirred at 60° C. for eight hours and at 85° C. for further 14 hours.Insoluble matters were removed by filtration, the filtrate wasevaporated to remove the solvent. The residue was purified by silica gelcolumn chromatography to obtain methyl2-[(4-methoxy-3-[(2S,3S,4R,5R,6R)-3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl]-1-naphthyl)methyl]azulene-1-carboxylate(0.34 g).

The compound of Example 62 was obtained in the same manner as in Example39.

Example 63

A 1 M aqueous solution of sodium hydroxide (12 ml) was added dropwise toa solution of methyl2-[3-[(1S)-1,5-anhydro-D-glucitol-1-yl]-4-methoxy-1-naphthyl]methylazulene-1-carboxylate(0.23 g) in methanol (8.0 ml) and the mixture was refluxed with heatingfor three hours. A 1 M aqueous solution of hydrochloric acid (12 ml) wasadded to the reaction mixture under cooling with ice and the solvent wasevaporated. The resulting residue was suspended in acetonitrile (15 ml).A 4 M 1,4-dioxane solution of hydrochloric acid (0.4 ml) was addeddropwise to the suspension and the mixture was refluxed with heating for15 minutes. The insoluble matter was removed by filtration and thesolvent was evaporated. The resulting residue was purified by silica gelcolumn chromatography and reverse phase column chromatography in thatorder to obtain(1S)-1,5-anhydro-1-[4-(azulen-2-ylmethyl)-1-methoxy-2-naphthyl]-D-glucitol(0.08 g).

The compounds of Examples 64, 65, and 66 were obtained respectively inthe same manner as in Examples 61, 39, and 63.

Example 67

Tris(dibenzylideneacetone)dipalladium (0) (17 mg),2-(dicyclohexylphosphino)biphenyl (22 mg), potassium fluoride (44 mg),and cesium carbonate (247 mg) were added to a solution of(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[5-(bromomethyl)-2-ethoxy-3-methoxyphenyl]-D-glucitol(327 mg) and methyl 2-(tributylstanyl)azulene-1-carboxylate (180 mg) in1,4-dioxane (10 ml). The mixture was vigorously stirred at 90° C. for 14hours. A 1 M aqueous solution of hydrochloric acid was added to thereaction mixture and the mixture was extracted with diethyl ether. Theorganic layer was washed with saturated brine and dried over anhydroussodium sulfate. After filtration, the filtrate was concentrated underreduced pressure. The resulting residue was dissolved in THF (4 ml) andMeOH (2 ml), and a 1 M aqueous solution of sodium hydroxide (0.5 ml) wasadded to the reaction mixture at room temperature. After stirring for 30minutes, a 1 M aqueous solution of sodium hydroxide (0.5 ml) was furtheradded to the reaction mixture. The mixture was stirred for 30 minutes.The solvent was evaporated under reduced pressure and the resultingresidue was purified by silica gel column chromatography(chloroform-methanol). Methanol (2.5 ml) and 10% aqueous solution ofsodium hydroxide (2.5 ml) were added to the resulting residue (133 mg)and the mixture was refluxed with heating for one hour. Afterevaporating the solvent under reduced pressure, ethanol was added. Themixture was filtered. The filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform-methanol) to obtain2-[4-ethoxy-3-methoxy-5-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]benzyl]azulene-1-carboxylicacid (51 mg).

Example 68

Acetonitrile and a 4 M ethyl acetate solution (0.02 ml) of hydrochloricacid (5 ml) were added to2-[4-ethoxy-3-methoxy-5-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]benzyl]azulene-1-carboxylic acid (50 mg) andthe mixture was refluxed with heating for 10 minutes. A 4 M ethylacetate solution (0.02 ml) of hydrochloric acid was further added to thereaction mixture and the mixture was refluxed with heating for 30minutes. The reaction mixture was concentrated under reduced pressure.The residue was purified by silica gel column chromatography(chloroform-methanol) to obtain(1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-ethoxy-3-methoxyphenyl]-D-glucitol(42 mg).

The compounds of Examples 69, 70, and 71 were obtained respectively inthe same manner as in Examples 61, 39, and 63.

Example 72

Tris(dibenzylideneacetone)dipalladium(0) (17 mg),2-(dicyclohexylphosphino)biphenyl (22 mg), potassium fluoride (44 mg),and cesium carbonate (247 mg) were added to a solution of(1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-(bromomethyl)-2-fluorophenyl]-D-glucitol (198 mg) and methyl2-(tributylstanyl)azulene-1-carboxylate (180 mg) in 1,4-dioxane (10 ml)and the mixture was vigorously stirred at 90° C. for 15 hours. Thereaction mixture was filtered through celite and the filtrate wasconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (ethyl acetate-n-hexane). Theresulting residue (71 ml) was dissolved in THF-methanol (ratio: 1:1, 6.0ml). Sodium methoxide (30 mg) was added to the solution and theresulting mixture was stirred at room temperature overnight. The solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (chloroform-methanol) to obtain methyl2-[2-fluoro-3-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]benzyl]azulene-1-carboxylate(19 mg).

Example 73

10% aqueous solution of sodium hydroxide (2 ml) was added to a solutionof methyl2-[2-fluoro-3-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]benzyl]azulene-1-carboxylate(19 mg) in methanol (2 ml). The mixture was refluxed with heating for 2hours. The reaction mixture was neutralized by adding a 4 M ethylacetate solution of hydrochloric acid and the solvent was evaporatedunder reduced pressure. Acetonitrile (5 ml) and a 4 M ethyl acetatesolution of hydrochloric acid (1 ml) were added to the resulting residueand the mixture was refluxed with heating for 30 minutes. The solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (chloroform-methanol) to obtain(1S)-1,5-anhydro-1-[3-(azulen-2-ylmethyl)-2-fluorophenyl]-D-glucitol (10mg).

The compound of Example 74 was obtained in the same manner as inReference Example 8.

Example 75

Aluminum chloride (0.12 g) and anisole (4.0 ml) were added to a solutionof(1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-(benzyloxy)phenyl]-2,3,4,6-tetra-O-benzyl-D-glucitol(0.07 g) in methylene chloride (5 ml) and the mixture was stirred atroom temperature for two hours. The reaction mixture was poured intoice-cooled water and extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous sodium sulfate.After filtration, the filtrate was concentrated. The residue waspurified by silica gel column chromatography (chloroform-methanol) toobtain(1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-hydroxyphenyl]-D-glucitol(0.01 g).

The structural formulas and physicochemical properties of the compoundsof Reference Examples and Examples are collectively shown by Tables 1–22at the end of the present specification.

The following abbreviations can be applied to the tables.

Rf refers to a number of Reference Example, Ex refers to a number ofExample, Structure refers to a structural formula, Ac refers to anacetyl group, Bn refers to a benzyl group, Bu refers to a butyl group,Data refers to a property data, NMR refers to a nuclear magneticresonance spectrum (TMS internal standard), and MS refers to a massanalysis value.

Compounds listed in Table 23 can be easily prepared by in the samemanner as in Examples and Preparation Examples or by a method with minormodifications which are obvious for persons having an ordinary skill inthe art. Table 23 is given after Tables 1–22.

Industrial Applicability

Since the azulene derivative and the salt thereof (the compounds of thepresent invention) have the effects of inhibiting a Na⁺-glucosecotransporter and reducing the level of blood glucose, these compoundsare useful for treating or preventing insulin-dependent diabetes (type 1diabetes), insulin-independent diabetes (type 2 diabetes),insulin-resistant diseases, and obesity, for example, as apharmaceutical, particularly as a Na⁺-glucose cotransporter inhibitor.

The significant effects of inhibiting a Na⁺-glucose cotransporter andreducing the blood glucose of the compound of the present invention havebeen confirmed in the following pharmacological tests (Test Examples 1and 2).

Test Example 1

[Inhibition of Human Na⁺-Glucose Cotransporter (Human SGLT2) Activity]

(1) Preparation of Human SGLT 2 Expression Vector

First, single-strand cDNA was reversely transcripted from total RNAoriginating from the human kidney (manufactured by BD BiosciencesClontech) using a Superscript II (manufactured by InvitrogenCorporation) and a random hexamer. Second, using the cDNA as a template,a DNA fragment encoding a human SGLT2 (Wells, R. G. et al., Am. J.Physiol., 1992, 263(3) F459) was amplified by the PCR reaction usingPyrobest DNA polymerase (manufactured by Takara Bio Inc.). That is, aHind III site and an EcoRI site were inserted into the 5′ side and the3′ side of the DNA fragment, respectively by using primers.

The amplified fragment was cloned into a pCR2.1-Topo vector using a TopoTA Cloning Kit (manufactured by Invitrogen Corporation) and the clonedvector was transfected into a competent cell of Escherichia coli JM109.Ampicillin-resistant clones were cultured in a LB medium containingampicillin (100 mg/l). A plasmid was purified from the culturedEscherichia coli using the method of Hanahan (see Maniatis et al.,“Molecular Cloning”). A DNA fragment for encoding a human SGLT2 wasobtained by the Hind III/EcoRI digestion of the plasmid and ligated andcloned to the same site of the expression vector pcDNA 3.1 (manufacturedby Invitrogen Corporation) using a DNA ligase (manufactured by RocheDiagnostics). The ligated clone was transfected into a competent cell ofEscherichia coli JM109 in the same manner as described above andcultured in a LB medium containing ampicillin, and a human SGLT2expression vector was obtained using the method of Hanahan.

(2) Preparation of Human SGLT2 Expressed Cells

The human SGLT2 expression vector was transfected into a CHO-K1 cellusing Lipofectamine2000 (manufactured by Invitrogen Corporation). Thecell was cultured in a Ham's F12 medium (manufactured by NissuiPharmaceutical Co., Ltd.) containing penicillin (50 IU/ml, manufacturedby Dainippon Pharmaceutical Co., Ltd.), streptomycin (50 μg/ml,manufactured by Dainippon Pharmaceutical Co., Ltd.), Geneticin (40μg/ml, manufactured by Invitrogen Corporation), and 10% fetal bovineserum in the presence of 5% CO₂ at 37° C. for two weeks, andGeneticin-resistant clones were obtained. A cell which stably expressesthe human SGLT2, which exhibits sodium-dependent intake ofmethyl-α-D-glucopyranoside, was obtained (See the following paragraphsfor the method for measuring the methyl-α-D-glucopyranoside intake).

(3) Inhibition of Methyl-α-D-Glucopyranoside Intake

After removing the medium of a CHO cell which stably expresses the humanSGLT2, a pretreatment buffer solution (buffer solution of pH 7.4containing choline chloride (140 mM), potassium chloride (2 mM), calciumchloride (1 mM), magnesium chloride (1 mM),2-[4-(2-hydroxyethyl)1-piperazinyl]ethanesulfonic acid (10 mM), andtris(hydroxymethyl) aminomethane (5 mM)) was added in the amount of 100μl per well, and incubated at 37° C. for 20 minutes.

11 μl of methyl-α-D-(U-14C) glucopyranoside (manufactured by AmershamPharmacia Biotech) was mixed with 1,000 μl of a buffer solution forintake containing a test compound (buffer solution of pH 7.4 containingsodium chloride (140 mM), potassium chloride (2 mM), calcium chloride (1mM), magnesium chloride (1 mM), methyl-α-D-glucopyranoside (50 μM),2-[4-(2-hydroxyethyl)1-piperazinyl]ethanesulfonic acid (10 mM), andtris(hydroxymethyl)aminomethane (5 mM)) to prepare a buffer solution forintake. A buffer solution for intake without a test compound wasprepared for a control group. A buffer solution for basal intake withouta test compound containing coline chloride (140 mM) instead of sodiumchloride for measuring the basal intake was prepared as well.

After removing the pretreatment buffer solution, the buffer solution forintake was added (25 μl per well) and incubated at 37° C. for two hours.After removing the buffer solution for intake, a buffer solution forwashing (buffer solution of pH 7.4 containing choline chloride (140 mM),potassium chloride (2 mM), calcium chloride (1 mM), magnesium chloride(1 mM), methyl-α-D-glucopyranoside (10 mM),2-[4-(2-hydroxyethyl)1-piperazinyl]ethanesulfonic acid (10 MM), andtris(hydroxymethyl)aminomethane (5 mM)) was added (200 μl per one well).The mixture was immediately removed. This washing operation was carriedout once more. 0.5% lauryl sodium sulfate was added (25 μl per well) tosolubilize the cells. 75 μl of Microscint 40 (manufactured byPerkinElmer, Inc.) was added to the solubilized cell and the radiationactivity was measured using a microscintillation counter TopCount(manufactured by PerkinElmer, Inc.). The value obtained by subtractingthe basal intake amount from the intake amount of the control group wasdefined as 100%. The concentration for 50% inhibition of the above value(IC₅₀ value) was calculated from a concentration-inhibition curve usingthe least squares method. As a result, the compound of the presentinvention exhibited a strong effect of inhibiting a Na+-glucosecotransporter. The IC₅₀ values of typical compounds of the presentinvention are shown in Table 24.

TABLE 24 Compound IC₅₀ (nM) Example 7 16 Example 11 29 Example 21 99Example 25 22 Example 28 16 Example 60 5.7 Example 75 8.9

Test Example 2

[Hypoglycemic Activity Confirmation Test]

Fed KK-A^(y) mice (CLEA Japan, Inc., male) were used. The test compoundwas suspended in 0.5% methylcellulose solution to a concentration of 3mg/10 ml. The weight of each mouse was measured. The test compoundsuspension was orally administered forcibly to the mice at a dose of 10ml/kg. Only 0.5% methylcellulose solution was administered to the miceof a control group. Each group consisted of six mice. Blood wascollected from the tail vein immediately before administering thecompound and one, two, four, and eight hours after administering thecompound. The blood glucose value was measured using a glucose CII TestWako (manufactured by Wako Pure Chemical Industries, Ltd.). Theintensity of hypoglycemic activity was determined by calculating thearea under the blood glucose value-time curve (AUC) using a trapezoidalmethod from the glucose value of 0–8 hours after administering thecompound and calculating the rate (%) of the decrease in the AUC of thedrug-administered group from that of the control group.

As a result, the compound of the present invention exhibited a stronghypoglycemic activity. The hypoglycemic activity of typical compounds ofthe present invention are shown in Table 25.

TABLE 25 Hypoglycemic Compound activity (%) Example 28 46 Example 60 45

The pharmaceutical composition containing one or more of the compoundsof the present invention and the pharmaceutically acceptable saltsthereof is prepared as a tablet, powder, fine granule, granule, capsule,pill, liquid, injection, suppository, ointment, adhesive, or the likeusing a carrier, vehicle, or other additives commonly used forpreparation and is orally or nonorally administered.

The amount of the compound of the present invention to be clinicallyadministered to the human body is appropriately determined, taking thesymptoms, weight, age, sex, and the like of a patient to which thecompound is administered into consideration, in the range of 0.1–500 mgper day for oral administration or in the range of 0.01–100 mg per dayfor nonoral administration, once or several times a day. Since theamount to be administered varies according to various conditions, it maybe sufficient to administer the compound at a smaller amount than theabove-described amount.

As a solid composition for oral administration of the compound of thepresent invention, a tablet, powder, granule, or the like is used. Insuch a solid composition, one or more active substances are mixed withat least one inert diluent such as lactose, mannitol, glucose,hydroxypropylcellulose, microcrystal cellulose, starch,polyvinylpyrrolidone, or magnesium aluminometasilicate. The compositionmay contain additives other than the inert diluent such as a lubricantsuch as magnesium stearate, a disintegrator such ascarboxymethylcellulose calcium, and a solubilizer such as glutamic acidand aspartic acid by a conventional method. The tablet or pill may beoptionally coated with a film of glucose or a stomach-soluble orintestines-soluble substance such as sucrose, gelatin,hydroxypropylcellulose, or hydroxypropyl-methylcellulose phthalate.

The liquid composition for oral administration includes pharmaceuticallyacceptable preparations such as an emulsion preparation, solutionpreparation, suspension preparation, syrup preparation, elixirpreparation, and the like and contains a commonly used inert diluentsuch as purified water and ethyl alcohol. The composition may contain,in addition to the diluent, adjuvants such as a solubilizer, humectant,and suspending agent, sweetener, flavorer, perfume, and preservative.

The injection for nonoral administration includes a sterilized aqueousor nonaqueous solution, suspension, and emulsion. Examples of thediluent for the aqueous solution or suspension include distilled waterand a physiological saline solution for injection. Examples of thediluent for the nonaqueous solution or suspension include propyleneglycol, polyethylene glycol, and vegetable oils such as olive oil;alcohols such as ethyl alcohol; and Polysolvate 80 (trade name). Such acomposition may further contain additives such as an isotonizing agent,preservative, humectant, emulsifier, dispersant, stabilizer (e.g.lactose), andsolubilizer. These compounds are sterilized by filteringthrough a bacteria-retaining filter and adding a disinfectant orirradiating, for example. These compounds maybe used by producing asterilized solid composition and dissolving the composition in asterilized water or injection solvent before using.

TABLE 1 Rf. Structure Data 1

¹H-NMR(CDCl₃): 2.63 (3H, s), 7.35–7.39 (1H,m), 7.50 (1H, t), 7.59 (1H,t), 7.67–7.86 (4H,m), 7.96 (1H, s), 8.43 (1H, d), 9.67 (1H, d) 2

¹H-NMR(CDCl₃): 2.63 (3H, s), 4.37 (2H, s),6.95–7.53 (8H, m), 8.14–8.17(2H, m) 3

¹H-NMR(CDCl₃): 2.56 (3H, s), 2.93 (1H, s),3.54–4.36 (8H, m), 4.40 (2H,s), 4.50–4.91 (6H,m), 6.87–7.56 (28H, m), 8.13 (3H, dd) 4

¹H-NMR(CDCl₃): 1.35 (3H, t), 1.42 (6H, d),3.01 (2H, q), 3.22 (1H, q),7.37 (1H, t), 7.46(1H, t), 7.67 (1H, d), 7.74 (1H, d), 7.78 (1H, d),7.88(1H, s), 7.97 (1H, s), 8.35 (1H, d), 9.76(1H,d) 5

¹H-NMR(CDCl₃): 1.30 (6H, d), 1.33 (3H, t),2.95–3.05 (3H, q), 4.39 (2H,s), 6.96 (1H, t),7.09–7.16 (2H, m), 7.28–7.31 (1H, m), 7.35–7.43 (2H,m), 7.59 (1H, s), 8.09–8.11 (2H, m) 6

¹H-NMR(CDCl₃): 1.24–1.29 (9H, t), 2.95–2.98(3H, q), 3.55–5.01 (17H, m),6.91–7.52 (26H,m), 7.60 (1H, s), 8.07 (1H, d), 8.16 (1H, d) 7

¹H-NMR(CDCl₃): 1.30 (3H, t), 2.27 (3H, s),3.73 (3H, dd), 3.84–4.01(5H,m), 4.10 (1H,t),4.20 (1H, m), 4.52 (2H, m), 4.67 (2H, m), 4.91(3H,m), 6.77 (1H, d), 6.98 (2H, m), 7.01 (1H,dd), 7.16–7.38 (19H, m)

TABLE 2 Rf. Structure Data  8

¹H-NMR(CDCl₃): 1.34 (3H, t), 2.28 (3H, s),3.60 (1H, m), 3.79 (4H, m),3.96 (3H, m), 4.40(1H, d), 4.53 (1H, d), 4.67 (2H, m), 4.63 (2H,m), 4.89(2H, m), 4.95 (1H, d), 6.76 (1H, d),6.90 (2H, m), 7.04 (1H, dd),7.15–7.35 (19H,m)  9

¹H-NMR(CDCl₃): 1.43 (3H, t), 1.77 (3H, s),2.01 (3H, s), 2.05 (3H, s),2.08 (3H, s), 2.27(3H, s), 3.83 (1H, m), 4.01 (2H, q), 4.14 (1H,m), 4.27(1H, dd), 4.93 (1H, d), 5.22 (1H, t),5.35 (2H, m), 6.73 (1H, d), 7.03(1H, d), 7.16(1H, s) 10

¹H-NMR(CDCl₃): 1.46 (3H, t), 1.78 (3H, s),2.01 (3H, s), 2.06 (3H, s),2.09 (3H, s), 3.84(1H, m), 4.05 (2H, q), 4.14 (1H, d), 4.27 (1H,dd),4.46 (1H, ABq), 4.48 (1H, ABq), 4.87 (1H,m), 5.22 (1H, m), 5.35 (2H, m),6.80 (1H, d),7.29 (1H, dd), 7.37 (1H, s) 11

¹H-NMR(CDCl₃): 2.53 (3H, s), 3.28 (6H, s),3.84–4.15 (6H, m), 4.34–4.90(8H, m), 5.36(1H, s), 6.95 (2H, d), 7.15–7.38 (20H, m), 7.80(1H, s) 12

ESI-MS(m/z): 673[M−H]⁻ 13

ESI-MS(m/z): 657[M−H]⁻ 14

¹H-NMR(CDCl₃): 2.41 (3H, s), 3.63 (2H, m),3.76–3.83 (5H, m), 3.90 (3H,s), 4.41 (1H, d),4.54–4.66 (4H, m), 4.86–4.94 (3H, m), 6.85(2H, m),7.15–7.36 (19H, m), 7.89 (1H, dd),8.17 (1H, d) 15

¹H-NMR(CDCl₃): 2.39 (3H, s), 3.45 (1H, s),3.62 (2H, m), 3.76–3.83 (4H,m), 4.37 (1H, d),4.53–4.65 (5H, m), 4.86–4.94 (3H, m), 6.86(2H, m),7.15–7.34 (20H, m), 7.44 (1H, s)

TABLE 3 Rf. Structure Data 16

¹H-NMR(CDCl₃): 2.37 (3H, s), 3.61 (2H, m),3.80 (4H, m), 4.37 (1H, d),4.48–4.66 (6H,m), 4.86–4.94 (3H, m), 6.88 (2H, m),7.12–7.35 (20H, m),7.51 (1H, s) 17

¹H-NMR(CDCl₃): 3.06 (1H, d), 3.36 (3H, s),3.50 (1H, dd), 3.73 (1H, m),3.82 (2H, m),3.90 (1H, d), 4.05 (1H, m), 4.18 (1H, m),4.39 (2H, s),4.48–4.67 (4H, m), 4.86 (1H, d),4.92 (2H, s), 6.98 (2H, m), 7.20–7.37(18H,m), 7.48 (1H, d), 7.49 (1H, d), 7.70 (1H, t) 18

¹H-NMR(CDCl₃): 3.36 (3H, s), 3.43 (1H, t),3.57–3 p.97 (5H, m), 4.37–4.97(10H, m),5.11 (1H, d), 6.94–7.81 (23H, m) 19

¹H-NMR(CDCl₃): 3.39 (3H, s), 3.49 (1H, m),3.62 (1H, m), 3.74–3.83 (4H,m), 4.33 (1H,d), 4.47–4.71 (7H, m), 4.87 (1H, d), 4.93 (2H,d), 6.88 (2H,m), 7.15–7.37 (18H, m), 7.67(1H, s), 7.82 (1H, s), 7.86 (1H, s), 9.97(1H,s) 20

¹H-NMR(CDCl₃): 3.37 (3H, s), 3.50 (1H, t),3.62 (1H, m), 3.77 (4H, m),4.26 (1H, d),4.43 (1H, d), 4.46 (2H, s), 4.55–4.72 (6H, m),4.87 (1H, d),4.90 (1H, d), 4.95 (1H, d), 6.91(2H, m), 7.18–7.54 (21H, m) 21

¹H-NMR(CDCl₃): 3.37 (3H, s), 3.50 (1H, t),3.60 (1H, m), 3.79 (5H, m),4.24 (1H, d),4.41–4.66 (8H, m), 4.86 (1H, d), 4.90 (1H, d),4.95 (1H, d),6.92 (2H, m), 7.18–7.41 (21H, m) 22

¹H-NMR(CDCl₃): 1.47 (1H, t), 3.48–3.81 (6H,m), 4.25–4.97 (8H, m),6.90–7.42 (34H, m)

TABLE 4 Rf. Structure Data 23

¹H-NMR(CDCl₃): 1.09 (9H, s), 3.47–3.80 (7H,m), 4.22–4.97 (8H, m), 4.88(2H, s), 6.88–7.70(34H, m) (1H, t) 24

¹H-NMR(CDCl₃): 1.47 (1H, t), 3.48–3.82 (7H,m), 4.25–4.97 (10H, m),6.90–7.42 (24H, m) 25

¹H-NMR(CDCl₃): 3.48–3.82 (7H, m), 4.23–4.97 (10H, m), 6.91–7.48 (24H, m)26

¹H-NMR(CDCl₃): 0.12 (6H, s), 0.96 (9H, s),3.79 (3H, s), 4.70 (2H, s),6.69 (1H, d), 7.31(1H, dd), 7.56 (1H, d) 27

¹H-NMR(CDCl₃): 0.93 (9H, s), 2.97 (1H, s),3.54–4.13 (9H, m), 4.36–4.93(10H, m), 6.81(1H, d), 7.01–7.75 (22H, m) 28

¹H-NMR(CDCl₃): 2.14 (1H, t), 3.46–3.84 (7H,m), 3.89 (3H, s), 4.19–4.97(10H, m), 6.88(1H, d), 6.93–7.38 (22H, m) 29

¹H-NMR(CDCl₃): 3.49–3.88 (7H, m), 3.91(3H, s), 4.17–4.96 (10H, m),6.85–7.41 (23H, m)

TABLE 5 Rf. Structure Data 30

¹H-NMR(CDCl₃): 3.03 (1H, s), 3.49–4.92(14H, m), 6.97–7.79 (24H, m) 31

¹H-NMR(CDCl₃): 3.41–3.84 (7H, m), 4.19–4.97 (8H, m), 6.97–7.79 (24H, m)32

¹H-NMR(CDCl₃): 0.84–1.55 (27H, m), 3.52–3.83 (7H, m), 4.21–4.96 (8H, m),6.88–7.54(24H, m) 33

¹H-NMR(CDCl₃): 3.45–3.86 (7H, m), 4.32–4.94 (8H, m), 6.86–7.93 (24H, m),9.97 (1H,s) 34

¹H-NMR(CDCl₃): 3.48–3.83 (7H, m), 4.24–4.98 (8H, m), 5.26 (1H, d), 5.75(1H, d), 6.74(1H, m), 6.89–7.50 (24H, m) 35

¹H-NMR(CDCl₃): 0.92 (9H, s), 7.05 (1H, t),7.18–7.24 (1H, m), 7.49 (1H,dd) 36

¹H-NMR(CDCl₃): 0.10 (6H, m), 0.94 (9H, s),3.56–4.89 (17H, m), 6.92–7.60(23H, m)

TABLE 6 Rf. Structure Data 37

ESI-MS(m/z): 666[M+NH₄]⁺ 38

¹H-NMR(CDCl₃): 3.60–4.00 (7H, m), 4.41–4.95(10H, m), 6.90–7.51 (23H, m)39

¹H-NMR(CDCl₃): 3.05 (1H, s), 3.48–4.15 (6H,m), 3.71 (3H, s), 4.50–4.92(8H, m), 6.99–7.38(23H, m) 40

¹H-NMR(CDCl₃): 3.40–4.19 (1H, m), 4.46–4.97(7H, m), 6.90–7.35 (23H, m)41

¹H-NMR(CDCl₃): 3.27–3.90 (6H, m), 3.79 (3H,s), 4.09 (1H, d), 6.97–7.01(2H, m), 7.19 (1H, t) 42

¹H-NMR(CDCl₃): 1.88 (3H, t), 2.00 (3H, s),2.06 (3H, s), 2.10 (3H, s),3.79 (3H, s), 3.80–3.84 (1H, m), 4.15–5.33 (6H, m), 6.84 (1H, t),6.99(1H, t), 7.06 (1H, t) 43

¹H-NMR(CDCl₃): 0.87–1.56 (27H, m), 1.80(3H, s), 2.00 (3H, s), 2.06 (3H,s), 2.08 (3H, s),3.80 (3H, s), 3.82–5.36 (7H, m), 6.83–6.95 (3H, m)

TABLE 7 Rf. Structure Data 44

ESI-MS(m/z): 320[M+H]⁺ 45

¹H-NMR(CDCl₃): 1.86 (3H, s), 2.04 (3H, s),2.06 (3H, s), 2.10 (3H, s),3.82–5.35 (7H, m),7.20–7.28 (2H, m), 7.46 (1H, d), 7.49 (1H, s) 46

¹H-NMR(CDCl₃): 0.87–1.56 (27H, m), 1.78(3H, s), 2.00 (3H, s), 2.06 (3H,s), 2.08 (3H, s),3.82–5.36 (7H, m), 7.30–7.41 (4H, m) 47

¹H-NMR(CDCl₃): 3.57–3.83 (6H, m), 3.76 (3H,s), 3.92 (3H, s), 4.03 (1H,d), 4.47–4.96 (8H, m),6.42 (1H, s), 6.90–7.34 (20H, m), 7.56 (1H, s) 48

¹H-NMR(CDCl₃): 3.33–3.75 (6H, m), 3.85 (3H,s), 3.89 (3H, s), 4.16 (1H,t), 4.41 (1H, d), 4.56(1H, d), 4.66 (1H, d), 4.74 (1H, d), 6.55 (1H,s),7.47 (1H, s) 49

¹H-NMR(CDCl₃): 2.84 (3H, s), 3.34 (3H, s),3.44 (3H, s), 3.45 (3H, s),3.57–3.92 (7H, m),3,83 (3H, s), 3.89 (3H, s), 4.24–4.92 (8H, m),6.43(1H, s), 7.54 (1H, s)

TABLE 8 Rf. Structure Data 50

¹H-NMR(CDCl₃): 0.87 (9H, t), 0.96–1.50 (18H,m), 2.82 (3H, s), 3.33 (3H,s), 3.45 (3H, s),3.46 (3H, s), 3.57–3.92 (7H, m), 3.75 (3H, s),3.83 (3H,s), 4.18–4.94 (8H, m), 6.36 (1H, s),7.25 (1H, s) 51

¹H-NMR(CDCl₃): 1.34 (3H, s), 1.36 (3H, s),1.76 (1H, t), 3.04–3.08 (1H,m), 5.09 (2H, d),7.14 (2H, d), 8.23 (2H, d) 52

¹H-NMR(CDCl₃): 1.33 (3H, s), 1.35 (3H, s),3.04–3.07 (1H, m), 4.95 (2H,s), 7.14 (2H, d),7.28 (2H, s), 8.23 (2H, d) 53

¹H-NMR(CDCl₃): 4.98 (2H, s), 7.20 (2H, t),7.37 (2H, s), 7.59 (1H, t),8.30 (2H, d) 54

¹H-NMR(CDCl₃): 0.87 (9H, t), 1.11–1.18 (6H,m), 1.27–1.38 (6H, m),1.51–1.58 (6H, m), 3.96(3H, s), 7.25 (1H, s), 7.42 (1H, t), 7.50 (1H,t),7.74 (1H, t), 8.37 (1H, d), 9.58 (1H, d) 55

¹H-NMR(CDCl₃): 1.38–1.46 (6H, m), 1.80 (3H,s), 2.01 (3H, s), 2.06 (3H,s), 2.07 (3H, s), 2.31(3H, s), 3.83 (1H, ddd), 4.00–4.29 (6H,m),4.55–4.65 (1H, m), 5.18–5.38 (3H, m), 6.64(1H, s), 6.86 (1H, s) 56

¹H-NMR(CDCl₃): 1.41–1.48 (6H, m), 1.82 (3H,s), 2.02 (3H, s), 2.07 (3H,s), 2.17 (3H, s), 3.90(1H, ddd), 4.02–4.30 (6H, m), 4.51 (1H, d),4.62(1H, d), 4.75–4.81 (1H, m), 5.20–5.42 (3H,m), 6.82 (1H, s), 6.90 (1H, s)

TABLE 9 Rf. Structure Data 57

¹H-NMR(CDCl₃): 1.44 (3H, t), 1.81 (3H, s),2.01 (3H, s), 2.04–2.08 (6H,m), 2.33 (3H, s),3.78–4.28 (8H, m), 4.55–4.66 (1H, m), 5.17–5.38 (3H,m), 6.63 (1H, s), 6.85 (1H, s) 58

¹H-NMR(CDCl₃): 1.46 (3H, t), 1.82 (3H, s),2.01 (3H, s), 2.07 (3H, s),2.07 (3H, s), 3.88–4.30 (8H, m), 4.52 (1H, d), 4.63 (1H, d), 4.76–4.82(1H, m), 5.21–5.41 (3H, m), 6.81 (1H, s),6.90 (1H, s) 59

¹H-NMR(CDCl₃): 2.27 (3H, d), 3.56–3.66 (2H,m), 3.71–3.94 (5H, m),4.44–4.68 (5H, m), 4.84–4.98 (3H, m), 6.87–7.37 (23H, m) 60

FAB-MS(m/z): 441[M+H]⁺ 61

EI-MS:519[M]⁺ 62

FAB-MS(m/z): 503[M+H]⁺ 63

EI-MS:581[M]⁺

TABLE 10 Rf. Structure Data 64

FAB-MS(m/z): 483[M+H]⁺ 65

FAB-MS(m/z): 562[M+H]⁺ 66

FAB-MS(m/z): 230[M+H]⁺ 67

¹H-NMR(CDCl₃): 2.16 (3H, s), 3.61 (2H, s),5.14 (2H, s), 6.88–7.67 (2H,dd), 7.32–7.48(6H, m) 68

FAB-MS(m/z): 404[M+H]⁺ 69

¹H-NMR(CDCl₃): 3.70–4.98 (19H, m), 6.89(2H, d), 3.44 (3H, s), 7.08–7.63(31H, m),8.11 (2H, d)

TABLE 11 Ex. Structure Data 1

¹H-NMR(CDCl₃): 2.55 (3H, s), 3.47–3.81 (7H,m), 4.11–4.32 (2H, m), 4.40(2H, s), 4.51–4.93(6H, m),, 6.86–7.46 (28H, m), 7.49 (1H, s),8.13 (2H,dd,)ESI-MS(m/z): 567[M+H]⁺ 2

¹H-NMR(CD₃OD): 2.57 (3H, s), 3.14–3.43 (5H,m), 3.66–3.70 (1H, m),3.96(1H, d), 4.35 (2H,s), 4.41–4.94 (4H, m),, 6.99–7.21 (6H, m), 7.54(1H,t), 7.60 (1H, s), 8.20 (1H, d), 8.34 (1H, d)EI-MS:393[M−H]⁻ 3

¹H-NMR(CDCl₃): 1.24–1.29 (9H, t), 2.92–3.01(3H, q), 3.40–4.94 (17H, m),6.85–8.08 (27H,m), 7.50 (1H, s), 8.17 (1H, d)ESI-MS(m/z): 811[M+H]⁺ 4

¹H-NMR(CD₃OD): 1.30 (6H, d), 1.32 (3H, t),2.99–3.04 (3H, q), 3.47–3.67(4H, m), 3.82–3.92(2H, ABq), 4.15 (1H, d), 4.43 (2H, s), 6.95(1H, t),7.18–7.28 (3H, m), 7.20 (1H, s), 7.42(1H, d), 7.56 (1H, d), 8.10 (1H,d), 8.15 (1H, s)EI-MS:450[M⁺] 5

¹H-NMR(CDCl₃): 1.46 (3H, t), 1.75 (3H, s),2.00 (3H, s), 2.03 (3H, s),2.05 (3H, s), 3.84(1H, m), 3.96 (3H, s), 4.03 (2H, q), 4.15 (1H,m), 4.28(1H, m), 4.54 (2H, s), 4.92 (1H, m),5.20 (1H, m), 5.35 (2H, m), 6.78(1H, d), 6.89(1H, s), 7.12 (1H, dd), 7.31 (1H, s), 7.38 (1H,t), 7.51(1H, t), 7.70 (1H, t), 8.28 (1H, d), 9.52(1H,d)ESI-MS(m/z): 651[M+H]⁺ 6

¹H-NMR(CD₃OD): 1.40 (3H, t), 3.39 (2H, m),3.49 (1H, m), 3.60 (1H, t),3.65 (1H, m), 3.85(1H, m), 4.05 (2H, m), 4.58 (2H, s), 4.69 (1H, d) 6.88(1H, d), 7.012 (1H, s), 7.15 (1H, dd),7.39 (1H, d), 7.43 (1H, t), 7.52(1H, t), 7.75(1H, t), 8.31 (1H, d), 9.50 (1H, d)ESI-MS(m/z): 469[M+H]⁺

TABLE 12 Ex. Structure Data  7

¹H-NMR(CD₃OD): 1.41 (3H, t), 2.13 (1H, brs),2.54 (1H, brs), 2.79 (1H,brs), 2.97 (1H, brs),3.55 (2H, m), 3.68 (2H, m), 3.81 (1H, m), 3.90(1H,m), 4.02 (1H, dd), 4.10 (1H, dd), 4.30 (2H,s), 4.75 (1H, d), 6.84 (1H,d), 7.15 (5H, m),7.39 (1H, d), 7.51 (1H, t), 7.52 (1H, t), 8.19(2H,d)ESI-MS(m/z): 425 [M+H]⁺  8

¹H-NMR(CDCl₃): 2.39 (3H, s), 3.62 (2H, m),3.74–3.84 (6H, m), 3.93 (3H,s), 4.33 (1H, d),4.47–4.64 (5H, m), 4.84–4.95 (3H, m), 6.85 (1H,s), 6.91(2H, d), 7.13–7.31 (21H, m), 7.45 (1H,s), 7.49 (1H, t), 7.67 (1H, m),8.00 (1H, d), 9.51(1H, d)ESI-MS(m/z): 813[M+H]⁺  9

¹H-NMR(CD₃OD): 2.33 (3H, s), 3.66–3.92 (6H,m), 4.45 (1H, d), 4.53 (2H,s), 6.94 (1H, s), 7.05(2H, m), 7.34 (2H, m), 7.46 (1H, t), 7.66 (1H,t),8.18 (1H, d), 9.38 (1H, d)ESI-MS(m/z): 453[M+H]⁺ 10

¹H-NMR(CD₃OD): 2.32 (3H, s), 3.57–3.88 (3H,m), 4.35 (1H, d), 4.46 (2H,s), 6.88 (1H, s), 7.11(2H, m), 7.27 (2H, m), 7.55 (1H, t), 7.68 (1H,t),8.15 (1H, d), 9.33 (1H, d)ESI-MS(m/z): 438[M+H]⁺ 11

¹H-NMR(CD₃OD): 2.39 (3H, s), 3.41 (2H, m),3.54 (2H, m), 3.68 (1H, m),3.87 (1H, d), 4.29(2H, s), 4.45 (1H, d), 7.10 (6H, m), 7.41 (1H,s), 7.50(1H, s), 8.17 (2H, d)ESI-MS(m/z): 395[M+H]⁺ 12

¹H-NMR(CD₃OD): 2.28 (3H, s), 3.45 (2H, m),3.64 (2H, m), 3.81 (3H, s),3.82 (2H, m), 4.39(3H, s), 4.55 (2H, d), 6.83 (1H, d), 6.94 (3H, d),7.25(4H, m), 7.33 (1H, t), 7.47 (1H, t), 7.68(1H, t), 8.27 (1H, d), 9.38(1H, d)ESI-MS(m/z): 543[M+H]⁺

TABLE 13 Ex. Structure Data 13

¹H-NMR(CD₃OD): 2.78 (3H, s), 3.33 (2H,m), 3.62 (2H, m), 3.81 (2H, m),4.40 (3H,s), 4.55 (2H, d), 6.79 (1H, d), 6.85 (3H, d),7.11 (4H, m), 7.40(1H, t), 7.47 (1H, t),7.70 (1H, t), 8.22 (1H, d), 9.55 (1H,d)ESI-MS(m/z): 529[M+H]⁺ 14

¹H-NMR(CD₃OD): 2.37 (3H, s), 3.31 (2H,m), 3.50 (2H, m), 3.64 (1H, dd),3.86 (1H,m), 4.13 (2H, s), 4.42 (3H, s), 6.90 (1H,dd), 7.02–7.21 (9H,m), 7.27 (1H, s), 7.48(1H, t), 8.12 (1H, d), 8.22 (1H, d)ESI-MS(m/z):485[M+H]⁺ 15

¹H-NMR(CDCl₃): 2.32 (3H, s), 3.57–3.88(3H, m), 4.35 (1H, d), 4.46 (2H,s), 6.88(1H, s), 7.11 (2H, m), 7.27 (2H, m), 7.55(1H, t), 7.68 (1H, t),8.15 (1H, d), 9.33(1H, d)ESI-MS(m/z): 438[M+H]⁺ 16

¹H-NMR(CD₃OD): 2.39 (4H, brs), 3.38(1H, m), 3.47 (1H, m), 3.60–3.80 (4H,m),3.84 (3H, s), 4.10 (1H, d), 4.35 (2H, s),4.53 (2H, s), 6.92 (1H, s),7.16 (1H, s),7.21 (1H, s), 7.25 (1H, m), 7.30 (1H, t),7.44 (1H, t), 7.64(1H, t), 8.17 (1H, d),9.39 (1H, d)ESI-MS(m/z): 532[M+H]⁺ 17

¹H-NMR(CD₃OD): 2.40 (2H, brs), 3.14(3H, s), 3.22 (1H, m), 3.45–3.67 (5H,m),4.02 (1H, d), 4.18 (2H, s), 4.21 (2H, s),4.97 (1H, brs), 5.21 (1H,brs), 6.99–7.06(5H, m), 7.20 (1H, s), 7.40 (1H, t), 7.30(1H, t), 8.05(2H, d)ESI-MS(m/z): 425[M+H]⁺ 18

¹H-NMR(CDCl₃): 1.43 (6H, t), 3.46–3.80(7H, m), 4.20–4.93 (14H, m),6.85–7.39(24H, m), 7.62 (2H, d), 8.77 (1H, s), 9.64(2H, d)ESI-MS(m/z):885[M+H]⁺

TABLE 14 Ex. Structure Data 19

¹H-NMR(CD₃OD): 1.36 (6H, t), 3.39–4.12(7H, m), 4.13 (2H, s), 4.36 (4H,dd), 7.03–7.28 (4H, m), 7.54 (2H, d), 8.66 (1H, s), 9.51(2H,d)ESI-MS(m/z): 523[M − H]⁻ 20

¹H-NMR(CD₃OD): 3.34–3.52 (4H, m), 3.71–3.93 (2H, m), 4.16 (1H, d), 4.40(2H, s),7.29–7.45 (4H, m), 7.88 (2H, d), 8.76 (1H, s)ESI-MS(m/z): 467[M− H]⁻ 21

¹H-NMR(CD₃OD): 3.34–3.89 (6H, m), 4.12(1H, d), 4.17 (2H, s),7.18 (2H,d), 7.19–7.38(6H, m), 7.77 (1H, t), 8.25 (2H, d)ESI-MS(m/z): 381[M + H]⁺22

¹H-NMR(CDCl₃): 3.52–3.82 (7H, m), 3.93(3H, s), 4.22–4.95 (10H, m),6.86–7.68 (28H,m), 8.04 (1H, d), 9.53 (1H, d)ESI-MS(m/z): 799[M + H]⁺ 23

¹H-NMR(CD₃OD): 3.42–3.93 (6H, m), 3.93(3H, s), 4.18 (1H, d), 4.63 (2H,s), 7.02 (1H, s), 7.02–7.33 (4H, m), 7.42 (1H, t), 7.53 (1H,t), 7.73(1H, t), 8.30 (1H, d), 9.48 (1H, d)ESI-MS(m/z): 423[M − H]⁻ 24

¹H-NMR(CD₃OD): 3.34–3.52 (4H, m), 3.70–3.93 (2H, m), 4.15 (1H, d), 4.69(2H, s), 7.06(1H, s), 7.24–7.84 (7H, m), 8.38 (1H, d),9.57 (1H,d)ESI-MS(m/z): 437[M − H]⁻ 25

¹H-NMR(CD₃OD): 3.34–3.93 (6H, m), 4.16(1H, d,J=9.3 Hz), 4.37 (2H, s),7.15–7.58(9H, m), 8.24 (2H, d)ESI-MS(m/z): 381[M + H]⁺

TABLE 15 Ex. Structure Data 26

¹H-NMR(CDCl₃): 1.74–2.09 (12H, m), 3.82 (3H,s), 3.96 (3H, s), 4.11–4.27(2H, m), 4.55 (2H, s),4.91–5.36 (5H, m), 6.79–7.69 (7H, m), 4.92 (1H,m),8.29 (1H, d), 9.53 (1H, d)ESI-MS(m/z): 637[M+H]⁺ 27

¹H-NMR(CD₃OD): 3.29–3.66 (5H, m), 3.78 (3H,s), 3.84 (1H, m), 4.55 (2H,s), 4.70 (1H, d), 6.88(1H, d), 6.98 (1H, s), 7.15 (1H, dd),7.37–7.42(1H, m), 7.49 (1H, t), 7.72 (1H, t), 8.28 (1H, d),9.48 (1H,d)ESI-MS(m/z): 435[M−H]⁻ 28

¹H-NMR(CD₃OD): 3.36–3.90 (6H, m), 3.86 (3H,s), 4.31 (2H, s), 4.74 (1H,d), 6.97 (1H, d), 7.15–7.43 (6H, m), 7.54 (1H, t), 8.23 (2H,d)ESI-MS(m/z): 411[M+H]⁺ 29

¹H-NMR(CDCl₃): 3.49–3.89 (7H, m), 3.94 (3H,s), 4.09–4.95 (10H, m),6.74–7.68 (24H, m),7.94 (1H, d), 9.52 (1H, d)ESI-MS(m/z): 851[M+Na]⁺ 30

¹H-NMR(CD₃OD): 3.29–4.56 (15H, m), 6.79–7.18 (4H, m), 7.41 (1H, t), 7.52(1H, t), 7.74(1H, t), 8.28 (1H, d), 9.42 (1H, d)ESI-MS(m/z): 469[M+H]⁺31

¹H-NMR(CD₃OD): 3.30–4.50 (7H, m), 3.80 (3H,s), 4.28 (2H, s), 6.92–7.31(6H, m), 7.48 (1H, t),8.16 (2H, d)ESI-MS(m/z): 477[M+Na]⁺ 32

¹H-NMR(CD₃OD): 3.30–4.29 (7H, m), 3.83 (3H,s), 4.30 (2H, s), 6.94–7.29(6H, m), 7.46 (1H, t),8.16 (2H, d)ESI-MS(m/z): 411[M+H]⁺

TABLE 16 Ex. Structure Data 33

¹H-NMR(CDCl₃): 3.57–3.89 (7H, m), 3.69 (3H,s), 4.35 (1H, d), 4.45 (1H,d), 4.56–5.00 (6H,m), 6.95–7.76 (28H, m), 8.36 (1H, d)ESI-MS(m/z):802[M+NH₄]⁺ 34

¹H-NMR(CD₃OD): 3.44–3.76 (5H, m), 3.77(3H, s), 3.89–3.92 (1H, m), 4.23(1H, d), 7.37–7.88 (8H, m), 8.47 (1H, d), 9.29 (1H, d)ESI-MS(m/z):442[M+NH₄]⁺ 35

¹H-NMR(CD₃OD): 3.52–3.86 (5H, m), 3.89–4.11 (1H, m), 4.17 (1H, d),7.33–7.88 (8H, m),8.52 (1H, d), 9.25 (1H, d)ESI-MS(m/z): 409[M−H]⁻ 36

¹H-NMR(CD₃OD): 3.49–3.73 (2H, m), 4.14(1H, d), 4.50 (1H, t), 4.88 (1H,d), 4.98 (2H,t), 7.23 (2H, t), 7.36 (1H, d), 7.44 (1H, t), 7.61(1H, t),7.82 (2H, s), 7.96 (1H, d), 8.00 (1H,s),8.38 (2H,d)ESI-MS(m/z):367[M+H]⁺ 37

¹H-NMR(CDCl₃): 1.63 (3H, s), 1.98(3H, s),2.05 (3H, s), 2.06 (3H, s),3.80–4.38 (4H, m),4.17 (2H, s), 5.12 (1H, t), 5.22 (1H, t), 5.31(1H, t),7.11–7.32 (8H, m), 7.51 (1H, t), 8.20(2H, d)ESI-MS(m/z): 549[M+H]⁺ 38

¹H-NMR(CDCl₃): 1.71 (3H, s), 2.07 (3H, s),2.08 (3H, s), 2.09 (3H, s),2.70 (3H, s), 3.80–4.38 (4H, m), 4.57 (2H, s), 5.11 (1H, t), 5.22(1H,t), 5.30 (1H, t), 6.84 (1H, s), 7.17–7.55(6H, m), 7.72 (1H, t), 8.28(1H, d), 9.35 (1H,d)ESI-MS(m/z): 589[M−H]⁻ 39

¹H-NMR(CD₃OD): 2.69 (3H, s), 3.30–3.87(6H, m), 4.10 (1H, d), 7.03 (1H,s), 7.12–7.46(4H, m), 7.49 (1H, t), 7.57 (1H, t), 7.79 (1H,t), 8.37 (1H,d), 9.30 (1H, d)ESI-MS(m/z): 423[M+H]⁺

TABLE 17 Ex Structure Data 40

¹H-NMR(CDCl₃): 1.81 (3H, t), 1.67 (3H, s),1.98 (3H, s), 2.05 (3H, s),2.08 (3H, s), 3.04(2H, dd), 3.60–4.36 (6H, m), 5.08–5.31 (3H,m),6.99–7.51 (8H, m), 8.09 (1H, d), 8.20(1H, d)ESI-MS(m/z): 577[M+H]⁺ 41

¹H-NMR(CD₃OD): 1.20 (3H, t), 3.07 (2H,dd), 3.30–3.88 (6H, m), 4.10 (1H,d), 4.31(2H, s), 7.00–7.45 (8H, m), 8.08 (1H, d), 8.22(1H,d)ESI-MS(m/z): 409[M+H]⁺ 42

¹H-NMR(CDCl₃): 3.08–3.12 (2H, m), 3.50–3.82 (9H, m), 3.95 (3H, s),4.13–4.97 (8H,m), 6.88–7.39 (26H, m), 7.50 (1H, t), 7.66(1H, t), 8.23(1H, d), 9.53 (1H, d)ESI-MS(m/z): 830[M+NH₄]⁺ 43

¹H-NMR(CD₃OD): 3.04 (2H, t), 3.30–3.89(8H, m), 3.89 (3H, s), 4.11 (1H,d), 7.17–7.31(5H, m), 7.48 (1H, t), 7.55 (1H, t), 7.78 (1H,t), 8.40 (1H,d), 9.44 (1H, d)ESI-MS(m/z): 453[M+H]⁺ 44

¹H-NMR(CD₃OD): 3.06–3.10 (2H, m), 3.30–3.89 (8H, m), 4.12 (1H, d),7.18–7.34 (5H,m), 7.46 (1H, t), 7.53 (1H, t), 7.76 (1H, t),8.39 (1H, d),9.50 (1H, d)ESI-MS(m/z): 439[M+H]⁺ 45

¹H-NMR(CD₃OD): 3.11 (2H, t), 3.27–3.89(8H, m), 4.11 (1H, d), 7.11–7.24(7H, m),7.33 (1H, s), 7.50 (1H, t), 8.20 (2H, d)ESI-MS(m/z): 395[M+H]⁺46

¹H-NMR(CDCl₃): 3.60–3.99 (7H, m), 3.91(3H, s), 4.43–4.93 (10H, m),6.85–7.44 (25H,m), 7.50 (1H, t), 7.68 (1H, t), 8.05 (1H, d),9.51 (1H,d)ESI-MS(m/z): 834[M+NH₄]⁺

TABLE 18 Ex. Structure Data 47

¹H-NMR(CD₃OD): 3.38–3.88 (6H, m), 3.93(3H, s), 4.48–4.51 (1H, m), 4.57(2H, s), 6.97(1H, dd), 7.06 (1H, s), 7.14–7.18 (1H, m),7.44–7.51 (2H,m), 7.56 (1H, t), 7.80 (1H, m),8.38 (1H, d), 9.46 (1H, d)ESI-MS(m/z):457[M+H]⁺ 48

¹H-NMR(CD₃OD): 3.38–3.87 (6H, m), 4.49–4.50 (1H, m), 4.61 (2H, s),6.96–7.56 (6H, m),7.77 (1H, t), 8.34 (1H, d), 9.52 (1H, d)ESI-MS(m/z):441[M−H]⁻ 49

¹H-NMR(CD₃OD): 3.34–3.88 (6H, m), 4.31(2H, s), 4.49–4.83 (1H, m),6.97–7.54 (8H, m),8.20 (2H, d)ESI-MS(m/z): 399[M+H]⁺ 50

¹H-NMR(CDCl₃): 1.63 (3H, s), 1.98 (3H, s),2.04 (3H, s), 2.06 (3H, s),3.78 (3H, s), 3.79–3.86 (1H, m), 4.09–5.31 (6H, m), 6.80–6.81(3H, m),7.11–7.16 (4H, m), 7.51 (1H, t), 8.20(2H, d)ESI-MS(m/z:579[M+H]⁺ 51

¹H-NMR(CD₃OD): 3.30–3.45 (4H, m), 3.69(1H, dd), 3.75 (3H, s), 3.85–3.89(1H, m), 4.08(1H, d), 4.29 (2H, s), 6.78 (1H, t), 6.85 (1H, t),6.97 (1H,t), 7.11–7.16 (4H, m), 7.50 (1H, t),8.19 (2H, d)ESI-MS(m/z): 433[M+Na]⁺52

¹H-NMR(CD₃OD): 3.42–3.93 (6H, m), 3.93(3H, s), 4.18 (1H, d), 4.33 (2H,s), 4.63 (2H,s), 7.02 (1H, s), 7.02–7.33 (8H, m), 7.42 (1H,t), 7.53 (1H,t), 7.73 (1H, t), 8.30 (1H, d), 9.48(1H, d)ESI-MS(m/z): 527[M−H]⁻ 53

¹H-NMR(CD₃OD): 3.31–3.87 (6H, m), 4.05(1H, d), 4.17 (2H, s), 4.42 (2H,s), 6.92–7.19(9H, m), 7.40 (1H, t), 7.51 (1H, t), 7.73 (1H,t), 8.40(1H,d), 9.51(1H, d)ESI-MS(m/z): 513[M−H]⁻

TABLE 19 Ex. Structure Data 54

¹H-NMR(CD₃OD): 3.31–3.88 (6H, m), 4.06(1H, d), 4.17 (2H, s), 4.42 (2H,s), 7.02–7.26(12H, m), 7.48 (1H, t), 8.14 (1H, d), 8.24(1H,d)ESI-MS(m/z): 471[M+H]⁺ 55

¹H-NMR(CDCL₃): 1.32 (3H, s), 1.33 (3H, s),1.63 (3H, s), 1.98 (3H, s),2.05 (3H, s), 2.06(3H, s), 3.01–3.05 (1H, m), 3.79–3.83 (1H,m),4.14–4.37 (5H, m), 5.11 (1H, t), 5.22(1H, t), 5.29 (1H, t), 7.05 (2H,s), 7.08 (2H,d), 7.20–7.31 (4H, m), 8.13 (2H, d)ESI-MS(m/z): 591[M+H]⁺56

¹H-NMR(CD₃OD): 1.32 (3H, s), 1.34 (3H,s), 3.02–3.05 (1H, m), 3.37–3.88(6H, m),4.11 (1H, d), 4.29 (2H, s), 7.06 (2H, s), 7.10(2H, d), 7.21–7.27(3H, m), 7.36 (1H, s),8.12 (2H, d)ESI-MS(m/z): 423[M+H]⁺ 57

¹H-NMR(CDCl₃): 1.32 (3H, s), 1.33 (3H, s),1.64 (3H, s), 1.98 (3H, s),2.05 (3H, s), 2.06(3H, s), 3.01–3.05 (1H, m), 3.77 (3H, s),3.78–3.81(1H, m), 4.11–4.34 (3H, m), 4.26(2H, s), 5.11 (1H, t), 5.22 (1H, t),5.28 (1H,t), 6.78 (3H, m), 7.04 (2H, s), 7.06 (2H, d)ESI-MS(m/z):621[M+H]⁺ 58

¹H-NMR(CD₃OD): 1.32 (3H, s), 1.34 (3H,s), 3.02–3.05 (1H, m), 3.36–3.43(4H, m),3.67 (1H, dd), 3.75 (3H, s), 3.78 (1H, d),3.85 (1H, dd), 4.08(1H, d), 4.25 (2H, s),6.77 (1H, d), 6.85 (1H, d), 6.96 (1H, s), 7.06(2H,s), 7.11 (2H, d), 8.12 (2H, d)ESI-MS(m/z): 453[M+H]^(;) 59

¹H-NMR(CDCl₃): 2.81 (3H, s), 3.24 (3H, s),3.431 (3H, s), 3.435 (3H, s),3.53–3.88 (6H,m), 4.18–4.91 (8H, m), 4.26 (1H, d), 6.44(1H, s), 7.10(2H, t), 7.15 (2H, s), 7.23 (1H,brs), 7.47 (1H, t), 8.14 (2H,d)EI-MS:616[M⁺]

TABLE 20 Ex. Structure Data 60

¹H-NMR(CD₃OD): 2.03 (1H, t), 2.12 (1H,brs), 2.60 (1H, brs), 2.77 (3H,brs), 3.45–3.80 (6H, m), 3.85 (3H, s), 3.87 (3H, s),4.23–4.33 (2H, ABq),4.69 (1H, d), 6.52(1H, s), 7.12 (2H, t), 7.15 (2H, s), 7.21 (1H,s), 7.49(1H, t), 8.17 (2H, d)EI-MS:440[M⁺] 61

¹H-NMR(CDCl₃): 1.75 (3H, s), 2.00 (3H, s),2.03 (3H, s), 2.08 (3H, s),3.95 (1H, m),4.04 (3H, s), 4.05 (3H, s), 4.16 (1H, dd),4.28 (1H, dd),4.90 (1H, d), 5.08–5.18 (2H,m), 5.26 (1H, t), 5.40–5.54 (2H, m),6.60(1H, s), 7.30 (1H, t), 7.38 (1H, t), 7.46–7.55(3H, m), 7.67 (1H, m),7.88 (1H, d), 8.09(1H, d), 8.15 (1H, d),9.56 (1H, d)ESI-MS(m/z):423[M+H]⁺ 62

¹H-NMR(CDCl₃): 3.85 (3H, s), 3.96 (3H, s),4.83 (1H, d), 4.96 (2H, s),6.63 (1H, s), 7.23(1H, t), 7.34–7.40 (2H, m), 7.43–7.50 (2H,m), 7.62(1H, t), 7.83 (1H, d), 8.02 (1H, d),8.12 (1H, d), 9.45 (1H,d)ESI-MS(m/z): 453[M+H]⁺ 63

¹H-NMR(CD₃OD): 3.41–3.52 (2H, m), 3.57(1H, t), 3.65–3.76 (2H, m), 3.89(1H, dd),4.00–4.03 (4H, m), 7.07–7.14 (4H, m), 7.40(1H, m), 7.44–7.51(2H, m), 7.59 (1H, s),8.01 (1H, d), 8.10–8.18 (3H, m)FAB-MS(m/z):461[M+H]⁺ 64

¹H-NMR(CDCl₃): 1.78 (3H, s), 2.02 (3H, s),2.04 (3H, s), 2.06 (3H, s),3.64 (3H, s), 3.72(3H, s), 3.80–3.92 (2H, s), 4.04 (3H, s), 4.12(1H,dd), 4.26 (1H, dd), 4.64 (2H, s), 4.82(1H, d), 5.24 (1H, t), 5.35 (1H,t), 5.48 (1H,t), 6.59 (1H, s), 6.80 (1H, d), 7.25–7.40 (3H,m), 7.50 (1H,t), 7.66 (1H, t), 8.11 (1H, d),9.52(1H, d)FAB-MS(m/z): 667[M+H]⁺ 65

¹H-NMR(CDCl₃): 3.53 (3H, s), 3.56 (3H, s),3.94 (3H, s),4.52 (2H, s),6.62 (1H, s), 6.72(1H, d), 7.18 (1H, t), 7.35–7.46 (2H, m),7.57 (1H, t),8.00 (1H, d), 9.45 (1H, d)FAB-MS(m/z): 499[M+H]⁺

TABLE 21 Ex. Structure Data 66

¹H-NMR(CD₃OD): 3.37–3.42 (2H, m), 3.44 (1H,m), 3.62 (1H, m), 3.65 (3H,s), 3.69 (1H, m),3.80 (3H, s), 3.84 (1H, m), 4.37 (2H, s), 4.53(1H, d),6.88 (1H, d), 7.06–7.13 (4H, m), 7.37(1H, d), 7.46 (1H, m), 8.12 (2H,d)FAB-MS(m/z): 441[M +H]⁺ 67

¹H-NMR(CD₃OD): 1.37 (3H, t), 2.98–3.10(1H,m), 3.30–3.70 (8H, m), 4.05(1H, d), 4.10 (1H,d), 4.58 (1H, d), 6.74 (1H, s), 6.89 (1H, s), 7.10(1H,s), 7.35 (1H, dd), 7.47 (1H, dd), 7.69 (1H,dd), 8.24 (1H, d), 9.46 (1H,d)FAB-MS(m/z): 497[M −H]⁻ 68

¹H-NMR(CD₃OD): 1.40 (3H, t), 3.07–3.16 (1H,m), 3.36–3.72 (5H, m), 3.74(3H, s), 4.10 (2H,q), 4.30 (1H, d), 4.46 (1H, d), 4.59 (1H, d), 6.81(1H,s), 7.09–7.18 (5H, m), 7.50 (1H, dd), 8.18(2H, d)FAB-MS(m/z): 455 [M+H]⁺ 69

¹H-NMR(CDCl₃): 1.39 (3H, t), 1.48 (3H, t),1.78 (3H, s), 1.96–2.00 (911,m), 3.42–4.33(11H, m), 4.51–5.45 (5H, m), 6.73 (1H, s), 6.76(1H, s),7.00 (1H, s), 7.37 (1H, t), 7.55 (1H, t),7.72 (1H, t), 8.12 (1H, d),9.54 (1H, d)FAB-MS(m/z): 695[M +H]⁺ 70

¹H-NMR(CD₃OD): 1.21 (3H, t), 1.31 (3H, t),3.18–3.23 (1H, m), 3.32–3.63(6H, m), 3.78–3.94 (5H, m), 4.02 (2H, q), 4.25 (1H, d), 4.44(1H, d),6.61 (1H, s), 6.84 (1H, s), 7.04 (1H, s),7.33 (1H, t), 7.44 (1H, t),7.66 (1H, t), 8.19(1H, d), 9.35 (1H, d)FAB-MS(m/z): 527[M +H]⁺ 71

¹H-NMR(CD₃OD): 1.23 (3H, t), 1.30 (3H, t),2.98–3.06 (1H, m), 3.25–3.64(5H, m), 3.87(2H, q), 4.00 (2H, q), 4.19 (1H, d), 4.36 (1H,d), 4.48 (1H,d), 6.93 (1H, s), 6.98–7.07 (5H,m), 7.40 (1H, t), 8.08 (1H,d)FAB-MS(m/z): 469[M +H]⁺ 72

¹H-NMR(CD₃OD): 3.19–3.50 (4H, m), 3.60 (1H,dd), 3.75–3.85(4H, m),4.45–4.55 (3H, m), 6.83–7.04 (3H, m), 7.26–7.52 (3H, m), 7.60–7.74(1H,m), 8.14–8.28 (1H, m), 9.29–9.41 (1H, m)FAB-MS(m/z): 457[M +H]⁺

TABLE 22 Ex. Structure Data 73

¹H-NMR(CD₃OD): 3.28–3.62 (5H, m), 3.77 (1H,dd), 4.24 (2H, s), 4.47 (1H,d), 6.96–7.17 (6H,m), 7.25–7.34 (1H, m), 7.40 (1H, d), 8.08 (2H,d)FAB-MS(m/z): 399 [M +H]⁺ 74

¹H-NMR(CDCl₃): 3.58–3.97 (7H, m), 4.29–4.99(12H, m), 6.85–7.49 (33H, m),8.08 (2H, d)FAB-MS(m/z): 848[M +H]⁺ 75

¹H-NMR(CD₃OD): 3.37–3.59 (4H, m), 3.70 (1H,dd), 3.82 (1H, dd), 4.23 (2H,s), 4.56 (1H, d),6.76 (1H, d), 7.02–7.16 (5H, m), 7.29 (1H, d),7.49 (1H,dd), 8.17 (2H, d)FAB-MS(m/z): 397[M +H]⁺

TABLE 23

1. An azulene derivative of following formula (I) or a salt thereof:

wherein R¹ to R⁴ individually represent a hydrogen atom, optionallysubstituted lower alkyl, —C(═O)-optionally substituted lower alkyl, or—optionally substituted lower alkylene-optionally substituted aryl, R⁵to R¹² individually represent a hydrogen atom, an optionally substitutedlower alkyl, halogen atom, —OH, —O-optionally substituted lower alkyl,-optionally substituted lower alkylene-OH, -optionally substituted loweralkylene-O-optionally substituted lower alkyl, —O-optionally substitutedlower alkylene-O-optionally substituted lower alkyl, —O-optionallysubstituted lower alkylene-optionally substituted aryl, -optionallysubstituted lower alkylene-O—C(═O)-optionally substituted lower alkyl,—COOH, nitro, cyano, amino, substituted amino, or —C(═O)—O-optionallysubstituted lower alkyl, and A represents a bond or an optionallysubstituted lower alkylene, wherein -A- may be bonded to any one of thepositions 1–8 of the azulene ring, and any two of R⁵, R⁶, and R⁷ mayform a benzene ring together with the adjacent carbon atoms, and whereinoptionally substituted chemical groups are substituted with a haloaenatom, —OH, -lower alkylene-OH, —COOH, —C(═O)—O-lower alkyl, nitro,cyano, or an amino group.
 2. The azulene derivative or the salt thereofaccording to claim 1, wherein the optionally substituted lower alkyl,—C(═O)-optionally substituted lower alkyl, and —optionally substitutedlower alkylene-optionally substituted aryl represented by R¹ to R⁴ inthe above formula (I) are respectively a lower alkyl, —C(═O)-loweralkyl, and -lower alkylene-aryl, the optionally substituted lower alkyl,—O-optionally substituted lower alkyl, -optionally substituted loweralkylene-OH, -optionally substituted lower alkylene-O-optionallysubstituted lower alkyl, —O-optionally substituted loweralkylene-optionally substituted alkyl, —O-optionally substituted loweralkylene-optionally substituted aryl, -optionally substituted loweralkylene-O—C(═O)-optionally substituted lower alkyl, and—C(═O)—O-optionally substituted lower alkyl represented by R⁵ to R¹² inthe formula (I) are respectively a lower alkyl or a halogen-substitutedlower alkyl, —O-lower alkyl, -lower alkylene-OH, -lower alkylene-O-loweralkyl, —O-lower alkylene-O-lower alkyl, —O-lower alkylene-aryl, -loweralkylene-O—C(═O)-lower alkyl, and —C(═O)—O-lower alkyl, wherein theoptionally substituted lower alkylene represented by A in the aboveformula (I) is a lower alkylene or a halogen-substituted lower alkylene,and wherein optionally substituted chemical groups are substituted witha halogen atom, —OH, -lower alkylene-OH, —COOH, —C(═O)—O-lower alkyl,nitro, cyano, or an amino group.
 3. The azulene derivative or the saltthereof according to claim 1, wherein the group represented by A in theabove formula (I) is a lower alkylene.
 4. The azulene derivative or thesalt thereof according to claim 3, wherein the group represented by A inthe above formula (I) is a methylene.
 5. The azulene derivative or thesalt thereof according to claim 1, wherein the groups represented by R¹to R⁴ in the above formula (I) are hydrogen atoms.
 6. The azulenederivative or the salt thereof according to claim 1, wherein the azulenederivative of the above formula (I) is at least one compound selectedfrom the group consisting of1,5-anhydro-1-[3-(azulen-2-ylmethyl)phenyl]hexytol,1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-methoxyphenyl]hexytol,1,5-anhydro-1-[3-(azulen-2-ylmethyl)-5-methoxyphenyl]hexytol,1,5-anhydro-1-[3-(azulen-2-ylmethyl)-4-methoxyphenyl]hexytol,1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-ethoxyphenyl]hexytol,1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-methylphenyl]hexytol,1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-hydroxyphenyl]hexytol,1,5-anhydro-[5-(azulen-2-ylmethyl)-2-fluorophenyl]hexytol,1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2,4-dimethoxyphenyl]hexytol, and1,5-anhydro-1-[4-(azulen-2-ylmethyl)-1-methoxy-2-naphthyl]hexytol.
 7. Apharmaceutical composition containing an effective amount of an azulenederivative of following formula (I) or a salt thereof:

wherein R¹ to R⁴ individually represent a hydrogen atom, optionallysubstituted lower alkyl, —C(═O)-optionally substituted lower alkyl, or-optionally substituted lower alkylene-optionally substituted aryl, R⁵to R¹² individually represent a hydrogen atom, an optionally substitutedlower alkyl, halogen atom, —OH, —O-optionally substituted lower alkyl,-optionally substituted lower alkylene-OH, -optionally substituted loweralkylene-O-optionally substituted lower alkyl, —O-optionally substitutedlower alkylene-O-optionally substituted lower alkyl, —O-optionallysubstituted lower alkylene-optionally substituted aryl, -optionallysubstituted lower alkylene-O—C(═O)-optionally substituted lower alkyl,—COOH, nitro, cyano, amino, substituted amino, or —C(═O)—O-optionallysubstituted lower alkyl, and A represents a bond or an optionallysubstituted lower alkylene, wherein -A- may be bonded to any one of thepositions 1–8 of the azulene ring, and any two of R⁵, R⁶, and R⁷ mayform a benzene ring together with the adjacent carbon atoms, and whereinoptionally substituted chemical groups are substituted with a halogenatom, —OH, -lower alkylene-OH, —COOH, —C(═O)—O-lower alkyl, nitro,cyano, or an amino group and pharamaceutically acceptabe adjuvants.
 8. Amethod of inhibiting a Na⁺-glucose cotransporter comprisingadministering an effective amount of the pharmaceutical compositionaccording to claim 7 to a patient in need thereof.
 9. A method fortreating diabetes comprising administering an effective amount of anazulene derivative of following formula (I) or a salt thereof to apatient in need thereof:

wherein R¹ to R⁴ individually represent a hydrogen atom, optionallysubstituted lower alkyl, —C(═O)-optionally substituted lower alkyl, or—optionally substituted lower alkylene-optionally substituted aryl, R⁵to R¹² individually represent a hydrogen atom, an optionally substitutedlower alkyl, halogen atom, —OH, —O-optionally substituted lower alkyl,-optionally substituted lower alkylene-OH, -optionally substituted loweralkylene-O-optionally substituted lower alkyl, —O-optionally substitutedlower alkylene-O-optionally substituted lower alkyl, —O-optionallysubstituted lower alkylene-optionally substituted aryl, -optionallysubstituted lower alkylene-O—C(═O)-optionally substituted lower alkyl,—COOH, nitro, cyano, amino, substituted amino, or —C(═O)—O-optionallysubstituted lower alkyl, and A represents a bond or an optionallysubstituted lower alkylene, wherein -A- may be bonded to any one of thepositions 1–8 of the azulene ring, and any two of R⁵, R⁶, and R⁷ mayform a benzene ring together with the adjacent carbon atoms, and whereinoptionally substituted chemical groups are substituted with a halogenatom, —OH, -lower alkylene-OH, —COOH, —C(═O)—O-lower alkyl, nitro,cyano, or an amino group.
 10. A method for treating diabetes comprisingadministering an effective amount of the azulene derivative or the saltthereof according to claim 9 to a patient in need thereof, wherein theoptionally substituted lower alkyl, —C(═O)-optionally substituted loweralkyl, and -optionally substituted lower alkylene-optionally substitutedaryl represented by R¹ to R⁴ in the above formula (I) are respectively alower alkyl, —C(═O)-lower alkyl, and -lower alkylene-aryl, theoptionally substituted lower alkyl, —O-optionally substituted loweralkyl, -optionally substituted lower alkylene-OH, -optionallysubstituted lower alkylene-O-optionally substituted lower alkyl,—O-optionally substituted lower alkylene-O-optionally substituted loweralkyl, —O-optionally substituted lower alkylene-optionally substitutedaryl, -optionally substituted lower alkylene-O—C(═O)-optionallysubstituted lower alkyl, and —C(═O)—O-optionally substituted lower alkylrepresented by R⁵ to R¹² in the formula (I) are respectively a loweralkyl or a halogen-substituted lower alkyl, —O-lower alkyl, -loweralkylene-OH, -lower alkylene-O-lower alkyl, —O-lower alkylene-O-loweralkyl, —O-lower alkylene-aryl, -lower alkylene-O—C(═O)-lower alkyl, and—C(═O)—O-lower alkyl, wherein the optionally substituted lower alkylenerepresented by A in the above formula (I) is a lower alkylene or ahalogen-substituted lower alkylene, and wherein optionally substitutedchemical groups are substituted with a halogen atom, —OH, -loweralkylene-OH, —COOH, —C(═O)—O-lower alkyl, nitro, cyano, or an aminogroup.